Publications by authors named "Shougang Zhuang"

160 Publications

1-Hydroxypyrene mediates renal fibrosis through aryl hydrocarbon receptor signalling pathway.

Br J Pharmacol 2021 Oct 8. Epub 2021 Oct 8.

School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.

Background And Purpose: In chronic kidney disease (CKD), patients inevitably reach end-stage renal disease and require renal replacement therapies. Emerging evidence suggests that CKD is associated with metabolite disorders. However, the molecular pathways targeted by metabolites remain enigmatic. Here, we describe roles of the metabolite 1-hydroxypyrene in mediating renal fibrosis.

Experimental Approach: We analysed 5406 urine and serum samples from patients with stage 1-5 CKD using metabolomics, and 1-hydroxypyrene was identified and validated using longitudinal and drug intervention cohorts as well as 5/6 nephrectomised and adenine-induced rats.

Key Results: We identified correlations between the urine and serum levels of 1-hydroxypyrene and the estimated glomerular filtration rate in patients with CKD onset and progression. Moreover, increased 1-hydroxypyrene levels in serum and kidney tissues correlated with decreased renal function in two rat models. Upregulated mRNA expression of aryl hydrocarbon receptors (AhR) and its target genes, including CYP1A1, CYP1A2, and CYP1B1, was observed in both patients and rats with progressive CKD. Our study further showed upregulated mRNA expression of AhR and its three target genes and upregulated nuclear AhR protein levels in mice and HK-2 cells treated with 1-hydroxypyrene, which caused accumulation of extracellular matrix components. Furthermore, treatment with AhR short hairpin RNA or flavonoids inhibited mRNA expression of AhR and its target genes in 1-hydroxypyrene-induced HK-2 cells and mice.

Conclusion And Implications: Metabolite 1-hydroxypyrene was demonstrated to mediate renal fibrosis through activation of the AhR signalling pathway. Therefore, targeting AhR may be an alternative therapeutic strategy for CKD progression.
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http://dx.doi.org/10.1111/bph.15705DOI Listing
October 2021

Prevalence and related factors of hyperuricaemia in Shanghai adult women of different ages: a multicentre and cross-sectional study.

BMJ Open 2021 Sep 16;11(9):e048405. Epub 2021 Sep 16.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China

Objective: Women in different age phases have different metabolism and hormone levels that influence the production and excretion of uric acid. We aimed to investigate the prevalence and related factors of hyperuricaemia among women in various age phases.

Study Design: Observational, cross-sectional study.

Setting: Data were obtained from women at three health check-up centres in Shanghai.

Participants: Adult women from three health check-up centres were recruited. Exclusion criteria were individuals with pregnancy, cancer, incomplete information. Finally, 11 601 participants were enrolled.

Results: The prevalence rates of hyperuricaemia of total subjects were 11.15% (95% CIs 10.57% to 11.72%). The prevalence of hyperuricaemia in 18-29, 30-39, 40-49, 50-59, 60-69 and ≥70 years old was 6.41% (95% CI 4.97% to 7.86%), 5.63% (4.71% to 6.55%), 6.02% (5.01%% to 7.03%), 11.51% (10.19% to 12.82%), 16.49% (15.03% to 17.95%) and 23.98% (21.56% to 26.40%), respectively. Compared with 18-29 years old, the ORs for hyperuricaemia in other age phases were 0.870 (95% CI 0.647 to 1.170, p=0.357), 0.935 (0.693 to 1.261, p=0.659), 1.898 (1.444 to 2.493, p<0.001), 2.882 (2.216 to 3.748, p<0.001) and 4.602 (3.497 to 6.056, p<0.001), respectively. During the 18-29 years old, the related factors for hyperuricaemia were obesity and dyslipidaemia. During the 30-59 years old, the related factors were obesity, dyslipidaemia, hypertension and chronic kidney disease (CKD). Over the 60 years old, the occurrence of hyperuricaemia was mainly affected by obesity, dyslipidaemia and CKD, while hypertension cannot be an impact factor for hyperuricaemia independently of obesity and dyslipidaemia.

Conclusion: After 50 years old, the prevalence of hyperuricaemia in Shanghai women has increased significantly and reaches the peak after 70. Obesity and dyslipidaemia are two main related factors for hyperuricaemia during all ages, while diabetes mellitus and nephrolithiasis have no relationship with hyperuricaemia throughout. CKD is an independent impact factor for hyperuricaemia after 30 years old.
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http://dx.doi.org/10.1136/bmjopen-2020-048405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449970PMC
September 2021

Requirement of Histone Deacetylase 6 for Interleukin-6 Induced Epithelial-Mesenchymal Transition, Proliferation, and Migration of Peritoneal Mesothelial Cells.

Front Pharmacol 2021 30;12:722638. Epub 2021 Aug 30.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Influenced by microenvironment, human peritoneal mesothelial cells (HPMCs) acquired fibrotic phenotype, which was identified as the protagonist for peritoneal fibrosis. In this study, we examined the role of histone deacetylase 6 (HDAC6) for interleukin-6 (IL-6) induced epithelial-mesenchymal transition (EMT), proliferation, and migration of HPMCs. The role of HDAC6 in IL-6-elicited EMT of HPMCs was tested by morphological observation of light microscope, immunoblotting, and immune-fluorescence assay; and the function of HDAC6 in proliferation and migration of HPMCs was examined by CCK-8 assay, wound healing experiment, and immunoblotting. IL-6 stimulation significantly increased the expression of HDAC6. Treatment with tubastatin A (TA), a highly selective HDAC6 inhibitor, or silencing of HDAC6 with siRNA decreased the expression of HDAC6. Moreover, TA or HDAC6 siRNA suppressed IL-6-induced EMT, as evidenced by decreased expressions of α-SMA, Fibronectin, and collagen I and the preserved expression of E-cadherin in cultured HPMCs. Mechanistically, HDAC6 inhibition suppressed the expression of transforming growth factor β (TGFβ) receptor I (TGFβRI), phosphorylation of Smad3, secretion of connective tissue growth factor (CTGF), and transcription factor Snail. On the other hand, the pharmacological inhibition or genetic target of HDAC6 suppressed HPMCs proliferation, as evidenced by the decreased optical density of CCK-8 and the expressions of PCNA and Cyclin E. The migratory rate of HPMCs also decreased. Mechanistically, HDAC6 inhibition blocked the activation of JAK2 and STAT3. Our study illustrated that IL-6-induced HDAC6 not only regulated IL-6 itself downstream JAK2/STAT3 signaling but also co-activated the TGF-β/Smad3 signaling, leading to the change of the phenotype and mobility of HPMCs. HDAC6 could be a potential therapeutic target for the prevention and treatment of peritoneal fibrosis.
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http://dx.doi.org/10.3389/fphar.2021.722638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435636PMC
August 2021

Blockade of Autophagy Prevents the Development and Progression of Peritoneal Fibrosis.

Front Pharmacol 2021 23;12:724141. Epub 2021 Aug 23.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in long-term peritoneal dialysis (PD) patients. Nevertheless, limited measures have been shown to be effective for the prevention and treatment of PF. Some views reveal that activation of autophagy ameliorates PF but others demonstrate that autophagy promotes PF. It is obvious that the role of autophagy in PF is controversial and further studies are needed. Here, we investigated the role of autophagy in rat models of PF and damaged cultured human peritoneal mesothelial cells (HPMCs). Autophagy was highly activated in fibrotic peritoneum from two PF rat models induced by 4.25% peritoneal dialysate fluid (PDF) and 0.1% chlorhexidine gluconate (CG). Blockade of autophagy with 3-MA effectively prevented PF in both models and reversed epithelial to mesenchymal transition (EMT) by down-regulating TGF-β/Smad3 signaling pathway and downstream nuclear transcription factors Slug and Snail. Treatment with 3-MA also inhibited activation of EGFR/ERK1/2 signaling pathway during PF. Moreover, 3-MA prominently decreased STAT3/NF-κB-mediated inflammatory response and macrophage infiltration, and prevented peritoneal angiogenesis through downregulation of β-catenin signal. In addition, TGF-β1 stimulation up-regulated autophagic activity as evidenced by the increased autophagosome . Exposure of HPMCs to TGF-β1 resulted in the induction of EMT and activation of TGF-β/Smad3, EGFR/ERK1/2 signaling pathways. Treatment with 3-MA blocked all these responses. In addition, delayed administration of 3-MA was effective in reducing EMT induced by TGF-β1. Taken together, our study indicated that autophagy might promote PF and 3-MA had anti-fibrosis effect and . These results suggest that autophagy could be a potential target on PF therapy for clinical patients with long-term PD.
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http://dx.doi.org/10.3389/fphar.2021.724141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419262PMC
August 2021

The Essential Role of PRAK in Preserving Cardiac Function and Insulin Resistance in High-Fat Diet-Induced Diabetes.

Int J Mol Sci 2021 Jul 27;22(15). Epub 2021 Jul 27.

Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI 02908, USA.

Regulated/activated protein kinase (PRAK) plays a crucial role in modulating biological function. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice exposed to a high-fat diet (HFD). Wild-type and PRAK mice at 8 weeks old were exposed to either chow food or HFD for a consecutive 16 weeks. Glucose tolerance tests and insulin tolerance tests were employed to assess insulin resistance. Echocardiography was employed to assess myocardial function. Western blot was used to determine the molecular signaling involved in phosphorylation of IRS-1, AMPKα, ERK-44/42, and irisin. Real time-PCR was used to assess the hypertrophic genes of the myocardium. Histological analysis was employed to assess the hypertrophic response, interstitial myocardial fibrosis, and apoptosis in the heart. Western blot was employed to determine cellular signaling pathway. HFD-induced metabolic stress is indicated by glucose intolerance and insulin intolerance. PRAK knockout aggravated insulin resistance, as indicated by glucose intolerance and insulin intolerance testing as compared with wild-type littermates. As compared with wild-type mice, hyperglycemia and hypercholesterolemia were manifested in PRAK-knockout mice following high-fat diet intervention. High-fat diet intervention displayed a decline in fractional shortening and ejection fraction. However, deletion of PRAK exacerbated the decline in cardiac function as compared with wild-type mice following HFD treatment. In addition, PRAK knockout mice enhanced the expression of myocardial hypertrophic genes including ANP, BNP, and βMHC in HFD treatment, which was also associated with an increase in cardiomyocyte size and interstitial fibrosis. Western blot indicated that deletion of PRAK induces decreases in phosphorylation of IRS-1, AMPKα, and ERK44/42 as compared with wild-type controls. Our finding indicates that deletion of PRAK promoted myocardial dysfunction, cardiac remodeling, and metabolic disorders in response to HFD.
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http://dx.doi.org/10.3390/ijms22157995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347374PMC
July 2021

The prognosis and risk factors of baseline high peritoneal transporters on patients with peritoneal dialysis.

J Cell Mol Med 2021 Sep 26;25(18):8628-8644. Epub 2021 Jul 26.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

The relationship between baseline high peritoneal solute transport rate (PSTR) and the prognosis of peritoneal dialysis (PD) patients remains unclear. The present study combined clinical data and basic experiments to investigate the impact of baseline PSTR and the underlying molecular mechanisms. A total of 204 incident CAPD patients from four PD centres in Shanghai between 1 January 2014 and 30 September 2020 were grouped based on a peritoneal equilibration test after the first month of dialysis. Analysed with multivariate Cox and logistic regression models, baseline high PSTR was a significant risk factor for technique failure (AHR 5.70; 95% CI 1.581 to 20.548 p = 0.008). Baseline hyperuricemia was an independent predictor of mortality (AHR 1.006 95%CI 1.003 to 1.008, p < 0.001) and baseline high PSTR (AOR 1.007; 95%CI 1.003 to 1.012; p = 0.020). Since uric acid was closely related to high PSTR and adverse prognosis, the in vitro experiments were performed to explore the underlying mechanisms of which uric acid affected peritoneum. We found hyperuricemia induced epithelial-to-mesenchymal transition (EMT) of cultured human peritoneal mesothelial cells by activating TGF-β1/Smad3 signalling pathway and nuclear transcription factors. Conclusively, high baseline PSTR induced by hyperuricaemia through EMT was an important reason of poor outcomes in CAPD patients.
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http://dx.doi.org/10.1111/jcmm.16819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435427PMC
September 2021

Iron deficiency exacerbates cisplatin- or rhabdomyolysis-induced acute kidney injury through promoting iron-catalyzed oxidative damage.

Free Radic Biol Med 2021 09 21;173:81-96. Epub 2021 Jul 21.

Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China. Electronic address:

Iron deficiency is the most common micronutrient deficiency worldwide. While iron deficiency is known to suppress embryonic organogenesis, its effect on the adult organ in the context of clinically relevant damage has not been considered. Here we report that iron deficiency is a risk factor for nephrotoxic intrinsic acute kidney injury of the nephron (iAKI). Iron deficiency exacerbated cisplatin-induced iAKI by markedly increasing non-heme catalytic iron and Nox4 protein which together catalyze production of hydroxyl radicals followed by protein and DNA oxidation, apoptosis and ferroptosis. Crosstalk between non-heme catalytic iron/Nox4 and downstream oxidative damage generated a mutual amplification cycle that facilitated rapid progression of cisplatin-induced iAKI. Iron deficiency also exacerbated a second model of iAKI, rhabdomyolysis, via increasing catalytic heme-iron. Heme-iron induced lipid peroxidation and DNA oxidation by interacting with Nox4-independent mechanisms, promoting p53/p21 activity and cellular senescence. Our data suggests that correcting iron deficiency and/or targeting specific catalytic iron species are strategies to mitigate iAKI in a wide range of patients with diverse forms of kidney injury.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.07.025DOI Listing
September 2021

IFT88 deficiency in proximal tubular cells exaggerates cisplatin-induced injury by suppressing autophagy.

Am J Physiol Renal Physiol 2021 09 12;321(3):F269-F277. Epub 2021 Jul 12.

Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia.

Primary cilia are widely regarded as specialized sensors in differentiated cells that have been implicated in the regulation of cell proliferation, differentiation, and viability. We have previously shown that shortening of primary cilia sensitizes cultured kidney tubular cells to cisplatin-induced apoptosis. Intraflagellar transport 88 (IFT88) is an essential component for ciliogenesis and maintenance. Here, we have further examined the effect of proximal tubule-specific IFT88 ablation on cisplatin-induced acute kidney injury (AKI). In this study, more severe AKI occurred in IFT88 knockout mice than age- and sex-matched wild-type mice. Mechanistically, cisplatin stimulated autophagy in kidney tubular cells as an intrinsic protective mechanism. However, renal autophagy was severely impaired in IFT88 knockout mice. In cultured HK-2 cells, cisplatin induced more apoptosis when IFT88 was knocked down. Tat-beclin 1 peptide, a specific autophagy activator, could partially prevent IFT88-associated cell death during cisplatin treatment, although cilium length was not improved significantly. Reexpression of IFT88 partially restored autophagy in IFT88 knockdown cells and suppressed apoptosis during cisplatin treatment. Taken together, these results indicate that defective autophagy in IFT88-deficient kidney cells and tissues contributes to the exaggerated AKI following cisplatin exposure. Almost every cell has one hair-like, nonmotile antenna projecting from the cell surface, named the primary cilium. In kidney tubular cells, the primary cilium has a protective role, but the underlying mechanism is unclear. This study shows that a short cilium leads to the suppression of autophagy, which is responsible for the heightened injury sensitivity. These findings provide the clues of how to manipulate primary cilium and autophagy to save kidneys.
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http://dx.doi.org/10.1152/ajprenal.00672.2020DOI Listing
September 2021

The Role and Mechanism of Histone Deacetylases in Acute Kidney Injury.

Front Pharmacol 2021 16;12:695237. Epub 2021 Jun 16.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Acute kidney injury (AKI) is a common clinical complication with an incidence of up to 8-18% in hospitalized patients. AKI is also a complication of COVID-19 patients and is associated with an increased risk of death. In recent years, numerous studies have suggested that epigenetic regulation is critically involved in the pathophysiological process and prognosis of AKI. Histone acetylation, one of the epigenetic regulations, is negatively regulated by histone deacetylases (HDACs). Increasing evidence indicates that HDACs play an important role in the pathophysiological development of AKI by regulation of apoptosis, inflammation, oxidative stress, fibrosis, cell survival, autophagy, ATP production, and mitochondrial biogenesis (MB). In this review, we summarize and discuss the role and mechanism of HDACs in the pathogenesis of AKI.
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http://dx.doi.org/10.3389/fphar.2021.695237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242167PMC
June 2021

Inhibition of EZH2 prevents acute respiratory distress syndrome (ARDS)-associated pulmonary fibrosis by regulating the macrophage polarization phenotype.

Respir Res 2021 Jul 3;22(1):194. Epub 2021 Jul 3.

Department of Internal Emergency Medicine and Critical Care, Shanghai East Hospital, Tong Ji University, 1800, Yuntai Road, Shanghai, 200120, China.

Background: We recently reported histone methyltransferase enhancer of zeste homolog 2 (EZH2) as a key epigenetic regulator that contributes to the dysfunction of innate immune responses to sepsis and subsequent lung injury by mediating the imbalance of macrophage polarization. However, the role of EZH2 in acute respiratory distress syndrome (ARDS)-associated fibrosis remains poorly understood.

Methods: In this study, we investigated the role and mechanisms of EZH2 in pulmonary fibrosis in a murine model of LPS-induced ARDS and in ex-vivo cultured alveolar macrophages (MH-S) and mouse lung epithelial cell line (MLE-12) by using 3-deazaneplanocin A (3-DZNeP) and EZH2 the small interfering (si) RNA.

Results: We found that treatment with 3-DZNeP significantly ameliorated the LPS-induced direct lung injury and fibroproliferation by blocking EMT through TGF-β1/Smad signaling pathway and regulating shift of macrophage phenotypes. In the ex-vivo polarized alveolar macrophages cells, treatment with EZH2 siRNA or 3-DZNeP suppressed the M1 while promoted the M2 macrophage differentiation through modulating the STAT/SOCS signaling pathway and activating PPAR-γ. Moreover, we identified that blockade of EZH2 with 3-DZNeP suppressed the epithelial to mesenchymal transition (EMT) in co-cultured bronchoalveolar lavage fluid (BALF) and mouse lung epithelial cell line through down-regulation of TGF-β1, TGF-βR1, Smad2 while up-regulation of Smad7 expression.

Conclusions: These results indicate that EZH2 is involved in the pathological process of ARDS-associated pulmonary fibrosis. Targeting EZH2 may be a potential therapeutic strategy to prevent and treat pulmonary fibrosis post ARDS.
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http://dx.doi.org/10.1186/s12931-021-01785-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255011PMC
July 2021

Critical roles of SMYD2 lysine methyltransferase in mediating renal fibroblast activation and kidney fibrosis.

FASEB J 2021 07;35(7):e21715

Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA.

SET and MYND domain protein 2 (SMYD2) is a lysine methyltransferase that mediates histone H3 lysine 36 trimethylation (H3K36me3) and acts as a regulator of tumorgenesis and cystic growth. However, its role in renal fibrosis remains unknown. In this study, we found that SMYD2 was highly expressed in the murine kidney of renal fibrosis induced by unilateral ureteral obstruction, and primarily located in interstitial fibroblasts and renal tubular epithelial cells. Pharmacological inhibition of SMYD2 with AZ505, a highly selective inhibitor of SMYD2, protected against renal fibrosis and inhibited activation/proliferation of renal interstitial fibroblasts and conversion of epithelial cells to a profibrotic phenotype in this model. In cultured renal interstitial fibroblasts, treatment with AZ505 or silencing of SMYD2 by specific siRNA also inhibited serum- or TGF-β1-induced activation and proliferation of renal interstitial fibroblasts. Mechanistic studies showed that SMYD2 inhibition reduced phosphorylation of several profibrotic signaling molecules, including Smad3, extracellular signal-regulated kinase 1/2, AKT, signal transducer and activator of transcription-3 and nuclear factor-κB in both injured kidney and cultured renal fibroblasts. AZ505 was also effective in suppressing renal expression of Snail and Twist, two transcriptional factors that mediate renal partial epithelial-mesenchymal transition and fibrosis. Conversely, AZ505 treatment prevented downregulation of Smad7, a renoprotective factor in vivo and in vitro. These results indicate that SMYD2 plays a critical role in mediating conversion of epithelial cells to a profibrotic phenotype, renal fibroblast activation and renal fibrogenesis, and suggest that SMYD2 may be a potential target for the treatment of chronic fibrosis in kidney disease.
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http://dx.doi.org/10.1096/fj.202000554RRRDOI Listing
July 2021

Nintedanib attenuates peritoneal fibrosis by inhibiting mesothelial-to-mesenchymal transition, inflammation and angiogenesis.

J Cell Mol Med 2021 May 5. Epub 2021 May 5.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Nintedanib, an Food and Drug Administration (FDA) approved multiple tyrosine kinase inhibitor, exhibits an anti-fibrotic effect in lung and kidneys. Its effect on peritoneal fibrosis remains unexplored. In this study, we found that nintedanib administration lessened chlorhexidine gluconate (CG)-induced peritoneal fibrosis and reduced collagen I and fibronectin expression. This coincided with suppressed phosphorylation of platelet-derived growth factor receptor, fibroblast growth factor receptors, vascular endothelial growth factor receptor and Src family kinase. Mechanistically, nintedanib inhibited injury-induced mesothelial-to-mesenchymal transition (MMT), as demonstrated by decreased expression of α-smooth muscle antigen and vimentin and preserved expression of E-cadherin in the CG-injured peritoneum and cultured human peritoneal mesothelial cells exposed to transforming growth factor-β1. Nintedanib also suppressed expression of Snail and Twist, two transcription factors associated with MMT in vivo and in vitro. Moreover, nintedanib treatment inhibited expression of several cytokines/chemokines, including tumour necrosis factor-α, interleukin-1β and interleukin-6, monocyte chemoattractant protein-1 and prevented infiltration of macrophages to the injured peritoneum. Finally, nintedanib reduced CG-induced peritoneal vascularization. These data suggest that nintedanib may attenuate peritoneal fibrosis by inhibiting MMT, inflammation, and angiogenesis and have therapeutic potential for the prevention and treatment of peritoneal fibrosis in patients on peritoneal dialysis.
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http://dx.doi.org/10.1111/jcmm.16518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256343PMC
May 2021

Clinical outcomes, quality of life, and costs evaluation of peritoneal dialysis management models in Shanghai Songjiang District: a multi-center and prospective cohort study.

Ren Fail 2021 Dec;43(1):754-765

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

The new Family-Community-Hospital (FCH) three-level comprehensive management aimed to improve the efficiency and scale of peritoneal dialysis (PD) to meet the increased population of end-stage renal disease (ESRD). Our study focused on the clinical outcomes, quality of life, and costs evaluation of this model in a multi-center and prospective cohort study. A total of 190 ESRD patients who commenced PD at Shanghai Songjiang District were enrolled. According to different PD management models, patients were divided into the Family-Community-Hospital three-level management model ( = 90) and the conventional all-course central hospital management model ( = 100). The primary outcome was clinical outcomes of PD. The secondary outcomes were health-related quality of life (HRQOL) and medical costs evaluation. Compared to conventional management, community-based FCH management achieved a similar dialysis therapeutic effect, including dropout rate ( = 0.366), peritonitis rate ( = 0.965), patient survival ( = 0.441), and technique survival ( = 0.589). Follow-up data showed that similar levels of the renal and peritoneal functions, serum albumin, cholesterol and triglyceride, PTH, serum calcium, and phosphorus between the two groups (all  > 0.05). HRQOL survey showed that the FCH management model helped to improve the psychological status of PD patients, including social functioning ( = 0.006), role-emotional ( = 0.032), and mental health ( = 0.036). FCH management also reduced the hospitalization ( = 0.009) and outpatient visits ( = 0.001) and saved annual hospitalization costs ( = 0.005), outpatient costs ( = 0.026), and transport costs ( = 0.006). Compared with conventional management, community-based FCH management achieved similar outcomes, improved psychological health, reduced medical budgets, and thus had a good social prospect.
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http://dx.doi.org/10.1080/0886022X.2021.1918164DOI Listing
December 2021

Porcine models of acute kidney injury.

Am J Physiol Renal Physiol 2021 06 26;320(6):F1030-F1044. Epub 2021 Apr 26.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Pigs represent a potentially attractive model for medical research. Similar body size and physiological patterns of kidney injury that more closely mimic those described in humans make larger animals attractive for experimentation. Using larger animals, including pigs, to investigate the pathogenesis of acute kidney injury (AKI) also serves as an experimental bridge, narrowing the gap between clinical disease and preclinical discoveries. This article compares the advantages and disadvantages of large versus small AKI animal models and provides a comprehensive overview of the development and application of porcine models of AKI induced by clinically relevant insults, including ischemia-reperfusion, sepsis, and nephrotoxin exposure. The primary focus of this review is to evaluate the use of pigs for AKI studies by current investigators, including areas where more information is needed.
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http://dx.doi.org/10.1152/ajprenal.00022.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285645PMC
June 2021

Correlation analysis between expression of histone deacetylase 6 and clinical parameters in IgA nephropathy patients.

Ren Fail 2021 Dec;43(1):684-697

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Background: It has been demonstrated that histone deacetylase 6 (HDAC6) is involved in various kidney diseases in experimental study. However, correlation between HDAC6 and clinical parameters in IgA nephropathy (IgAN) patients is still unknown.

Methods: A total of 46 human kidney biopsy specimens with IgAN were selected as observation group, specimens of normal renal cortex tissue that was not affected by the tumor from patients with renal carcinoma ( = 7) served as control. We investigated the relationship between HDAC6 and clinical parameters in IgAN.

Results: HDAC6 was highly expressed in human kidney biopsy specimens with IgAN compared with control group, while the number of acetyl histone H3 positive cells were significantly decreased. There was a statistical difference in the indexes of albumin, estimated glomerular filtration rate (eGFR), serum urea, serum creatinine, serum uric acid, β2-microglobulin, cystatin C, cholesterol, high-density lipoprotein, low-density lipoprotein, and HDAC6 positive area among the different Oxford Classification ( < 0.05). The expression of HDAC6 was different in various eGFR levels, the expression of HDAC6 increased with the decreasing of eGFR level, the expression of acetyl histone H3 decreased with the decreasing of eGFR level. In addition, the expression of HDAC6 positively correlated with Masson trichrome positive area, serum urea, serum creatinine, β2 macroglobulin, and cystatin C, while negatively correlated with eGFR and acetyl histone H3. Multivariate linear regression analysis demonstrated that eGFR and cystatin C were independently associated with HDAC6, respectively ( < 0.05).

Conclusions: These results suggested that high level of HDAC6 expression in IgAN is correlated with renal dysfunction.
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http://dx.doi.org/10.1080/0886022X.2021.1914657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079031PMC
December 2021

Vascular endothelial growth factor-mediated peritoneal neoangiogenesis in peritoneal dialysis.

Perit Dial Int 2021 Apr 7:8968608211004683. Epub 2021 Apr 7.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Peritoneal dialysis (PD) is an important renal replacement therapy for patients with end-stage renal diseases, which is limited by peritoneal neoangiogenesis leading to ultrafiltration failure (UFF). Vascular endothelial growth factor (VEGF) and its receptors are key angiogenic factors involved in almost every step of peritoneal neoangiogenesis. Impaired mesothelial cells are the major sources of VEGF in the peritoneum. The expression of VEGF will be up-regulated in specific pathological conditions in PD patients, such as with non-biocompatible peritoneal dialysate, uremia and inflammation, and so on. Other working cells (i.e. vascular endothelial cells, macrophages and adipocytes) can also stimulate the secretion of VEGF. Meanwhile, hypoxia and activation of complement system further aggravate peritoneal injury and contribute to neoangiogenesis. There are several signalling pathways participating in VEGF-mediated peritoneal neoangiogenesis including tumour growth factor-β, Wnt/β-catenin, Notch and interleukin-6/signal transducer and activator of transcription 3. Moreover, VEGF is highly expressed in dialysate effluent of long-term PD patients and is associated with peritoneal transport function, which supports its role in the alteration of peritoneal structure and function. In this review, we systematically summarize the angiogenic effect of VEGF and evaluate it as a potential target for the prevention of peritoneal neoangiogenesis and UFF. Preservation of the peritoneal membrane using targeted therapy of VEGF-mediated peritoneal neoangiogenesis may increase the longevity of the PD modality for those who require life-long dialysis.
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http://dx.doi.org/10.1177/08968608211004683DOI Listing
April 2021

Histone Methyltransferase EZH2: A Potential Therapeutic Target for Kidney Diseases.

Front Physiol 2021 18;12:640700. Epub 2021 Feb 18.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme that catalyzes the addition of methyl groups to histone H3 at lysine 27, leading to gene silencing. Mutation or over-expression of EZH2 has been linked to many cancers including renal carcinoma. Recent studies have shown that EZH2 expression and activity are also increased in several animal models of kidney injury, such as acute kidney injury (AKI), renal fibrosis, diabetic nephropathy, lupus nephritis (LN), and renal transplantation rejection. The pharmacological and/or genetic inhibition of EZH2 can alleviate AKI, renal fibrosis, and LN, but potentiate podocyte injury in animal models, suggesting that the functional role of EZH2 varies with renal cell type and disease model. In this article, we summarize the role of EZH2 in the pathology of renal injury and relevant mechanisms and highlight EZH2 as a potential therapeutic target for kidney diseases.
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http://dx.doi.org/10.3389/fphys.2021.640700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930071PMC
February 2021

Pharmacologic Targeting of BET Proteins Attenuates Hyperuricemic Nephropathy in Rats.

Front Pharmacol 2021 16;12:636154. Epub 2021 Feb 16.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Hyperuricemia is an independent risk factor for renal damage and promotes the progression of chronic kidney disease. In this study, we investigated the effect of I-BET151, a small-molecule inhibitor targeting the bromodomain and extraterminal (BET) proteins, on the development of hyperuricemic nephropathy (HN), and the mechanisms involved. Expression levels of bromodomain-containing protein 2 and 4, but not 3 were increased in the kidney of rats with HN; administration of I-BET151 effectively prevented renal dysfunction, decreased urine microalbumin, and attenuated renal fibrosis as indicated by reduced activation of renal interstitial fibroblasts and expression of fibronectin and collagen I in HN rats. Mechanistic studies show that I-BET151 treatment inhibited transition of renal epithelial cells to a mesenchymal cell type as evidenced by preservation of E-cadherin and reduction of vimentin expression. This was coincident with reduced expression of TGF-β1 and dephosphorylation of Smad3 and ERK1/2. I-BET151 was also effective in inhibiting phosphorylation of NF-κB, expression of multiple cytokines and chemokines, and infiltration of macrophages to the injured kidney. Although there were increased serum levels of uric acid and xanthine oxidase, an enzyme that catalyzes production of uric acid, and decreased expression of renal organic anion transporter 1 and 3 that promote urate excretion in the model of HN, and reduced expression levels of urine uric acid, I-BET151 treatment did not affect these responses. Collectively, our results indicate that I-BET151 alleviates HN by inhibiting epithelial to mesenchymal transition and inflammation in association with blockade of TGF-β, ERK1/2 and NF-κB signaling.
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http://dx.doi.org/10.3389/fphar.2021.636154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921804PMC
February 2021

Synergistic Inhibition of Renal Fibrosis by Nintedanib and Gefitinib in a Murine Model of Obstructive Nephropathy.

Kidney Dis (Basel) 2021 Jan 23;7(1):34-49. Epub 2020 Aug 23.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Background: Our recent studies demonstrated that both nintedanib, an FDA-approved quadruple kinase inhibitor, and gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, protect against obstructive kidney disease. It remains unknown whether they have a synergistic effect.

Methods: In this study, we investigated the effect of combined administration of nintedanib and gefitinib on renal fibrosis in a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO).

Results: Combined treatment with nintedanib and gefitinib after UUO resulted in a greater antifibrotic effect compared with their individual application. Mechanistically, administration of nintedanib blocked UUO-induced phosphorylation of multiple kinase receptors associated renal fibrosis, including platelet-derived growth factor receptors, fibroblast growth factor receptors, vascular endothelial growth factor receptors, and Src family kinase, while gefitinib inhibited EGFR phosphorylation. Their combination also exhibited a more pronounced effect in reducing expression of tissue inhibitors of metalloproteinase-2 (TIMP-2), increasing expression of matrix metalloproteinase-2 (MMP-2), and suppressing renal proinflammatory cytokine expression and macrophage infiltration in the injured kidney. Furthermore, simultaneous administration of nintedanib and gefitinib was more potent in inhibiting UUO-induced renal phosphorylation of signal transducer and activator of transcription-3 (STAT3), nuclear factor-κB, and Smad-3 compared with monotherapy. In cultured renal interstitial fibroblasts, cotreatment with these 2 inhibitors also had synergistic effects in abrogating transforming growth factor β1-induced activation of renal fibroblasts and phosphorylation of Akt, STAT3, and Smad3.

Conclusions: Combined application of nintedanib and gefitinib has a synergistic antifibrotic effect in the kidney and may hold translational potential for the treatment of chronic kidney disease.
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http://dx.doi.org/10.1159/000509670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879279PMC
January 2021

Epidermal Growth Factor Receptor: A Potential Therapeutic Target for Diabetic Kidney Disease.

Front Pharmacol 2020 26;11:598910. Epub 2021 Jan 26.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease worldwide and the major cause of renal failure among patients on hemodialysis. Numerous studies have demonstrated that transient activation of epidermal growth factor receptor (EGFR) pathway is required for promoting kidney recovery from acute injury whereas its persistent activation is involved in the progression of various chronic kidney diseases including DKD. EGFR-mediated pathogenesis of DKD is involved in hemodynamic alteration, metabolic disturbance, inflammatory response and parenchymal cellular dysfunction. Therapeutic intervention of this receptor has been available in the oncology setting. Targeting EGFR might also hold a therapeutic potential for DKD. Here we review the functional role of EGFR in the development of DKD, mechanisms involved and the perspective about use of EGFR inhibitors as a treatment for DKD.
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http://dx.doi.org/10.3389/fphar.2020.598910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870700PMC
January 2021

Histone demethylase JMJD3 protects against renal fibrosis by suppressing TGFβ and Notch signaling and preserving PTEN expression.

Theranostics 2021 1;11(6):2706-2721. Epub 2021 Jan 1.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.

The Jumonji domain containing-3 (JMJD3), a specific histone demethylase for trimethylation on histone H3 lysine 27 (H3K27me3), is associated with the pathogenesis of many diseases, but its role in renal fibrosis remains unexplored. Here we examined the role of JMJD3 and mechanisms involved in the activation of renal fibroblasts and development of renal fibrosis. Murine models of 5/6 surgical nephrectomy (SNx) and ureteral unilateral obstruction (UUO) were used to assess the effect of a specific JMJD3 inhibitor, GSKJ4, and genetic deletion of JMJD3 from FOXD1 stroma-derived renal interstitial cells on the development of renal fibrosis and activation of renal interstitial fibroblasts. Cultured rat renal interstitial fibroblasts (NRK-49F) and mouse renal tubular epithelial cells (mTECs) were also used to examine JMJD3-mediated activation of profibrotic signaling. JMJD3 and H3K27me3 expression levels were upregulated in the kidney of mice subjected to SNx 5/6 and UUO. Pharmacological inhibition of JMJD3 with GSKJ4 or genetic deletion of JMJD3 led to worsening of renal dysfunction as well as increased deposition of extracellular matrix proteins and activation of renal interstitial fibroblasts in the injured kidney. This was coincident with decreased expression of Smad7 and enhanced expression of H3K27me3, transforming growth factor β1 (TGFβ1), Smad3, Notch1, Notch3 and Jagged1. Inhibition of JMJD3 by GSK J4 or its specific siRNA also resulted in the similar responses in cultured NRK-49F and mTECs exposed to serum or TGFβ1. Moreover, JMJD3 inhibition augmented phosphorylation of AKT and ERK1/2 and . These results indicate that JMJD3 confers anti-fibrotic effects by limiting activation of multiple profibrotic signaling pathways and suggest that JMJD3 modulation may have therapeutic effects for chronic kidney disease.
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http://dx.doi.org/10.7150/thno.48679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806480PMC
July 2021

Histone deacetylase 6 inhibition mitigates renal fibrosis by suppressing TGF-β and EGFR signaling pathways in obstructive nephropathy.

Am J Physiol Renal Physiol 2020 12 26;319(6):F1003-F1014. Epub 2020 Oct 26.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

We have recently shown that histone deacetylase 6 (HDAC6) is critically involved in the pathogenesis of acute kidney injury. Its role in renal fibrosis, however, remains unclear. In this study, we examined the effect of ricolinostat (ACY-1215), a selective inhibitor of HDAC6, on the development of renal fibrosis in a murine model induced by unilateral ureteral obstruction (UUO). HDAC6 was highly expressed in the kidney following UUO injury, which was coincident with deposition of collagen fibrils and expression of α-smooth muscle actin, fibronectin, and collagen type III. Administration of ACY-1215 reduced these fibrotic changes and inhibited UUO-induced expression of transforming growth factor-β1 and phosphorylation of Smad3 while increasing expression of Smad7. ACY-1215 treatment also suppressed phosphorylation of epidermal growth factor receptor (EGFR) and several signaling molecules associated with renal fibrogenesis, including AKT, STAT3, and NF-κB in the injured kidney. Furthermore, ACY-1215 was effective in inhibiting dedifferentiation of renal fibroblasts to myofibroblasts and the fibrotic change of renal tubular epithelial cells in culture. Collectively, these results indicate that HDAC6 inhibition can attenuate development of renal fibrosis by suppression of transforming growth factor-β1 and EGFR signaling and suggest that HDAC6 would be a potential therapeutic target for the treatment of renal fibrosis.
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http://dx.doi.org/10.1152/ajprenal.00261.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792693PMC
December 2020

New Insights Into the Role and Mechanism of Partial Epithelial-Mesenchymal Transition in Kidney Fibrosis.

Front Physiol 2020 15;11:569322. Epub 2020 Sep 15.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Epithelial-mesenchymal transition (EMT) is described as the process in which injured renal tubular epithelial cells undergo a phenotype change, acquiring mesenchymal characteristics and morphing into fibroblasts. Initially, it was widely thought of as a critical mechanism of fibrogenesis underlying chronic kidney disease. However, evidence that renal tubular epithelial cells can cross the basement membrane and become fibroblasts in the renal interstitium is rare, leading to debate about the existence of EMT. Recent research has demonstrated that after injury, renal tubular epithelial cells acquire mesenchymal characteristics and the ability to produce a variety of profibrotic factors and cytokines, but remain attached to the basement membrane. On this basis, a new concept of "partial epithelial-mesenchymal transition (pEMT)" was proposed to explain the contribution of renal epithelial cells to renal fibrogenesis. In this review, we discuss the concept of pEMT and the most recent findings related to this process, including cell cycle arrest, metabolic alternation of epithelial cells, infiltration of immune cells, epigenetic regulation as well as the novel signaling pathways that mediate this disturbed epithelial-mesenchymal communication. A deeper understanding of the role and the mechanism of pEMT may help in developing novel therapies to prevent and halt fibrosis in kidney disease.
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http://dx.doi.org/10.3389/fphys.2020.569322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522479PMC
September 2020

Class IIa HDAC inhibitor TMP195 alleviates lipopolysaccharide-induced acute kidney injury.

Am J Physiol Renal Physiol 2020 12 5;319(6):F1015-F1026. Epub 2020 Oct 5.

Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island.

Sepsis-associated acute kidney injury (SA-AKI) is associated with high mortality rates, but clinicians lack effective treatments except supportive care or renal replacement therapies. Recently, histone deacetylase (HDAC) inhibitors have been recognized as potential treatments for acute kidney injury and sepsis in animal models; however, the adverse effect generated by the use of pan inhibitors of HDACs may limit their application in people. In the present study, we explored the possible renoprotective effect of a selective class IIa HDAC inhibitor, TMP195, in a murine model of SA-AKI induced by lipopolysaccharide (LPS). Administration of TMP195 significantly reduced increased serum creatinine and blood urea nitrogen levels and renal damage induced by LPS; this was coincident with reduced expression of HDAC4, a major isoform of class IIa HDACs, and elevated histone H3 acetylation. TMP195 treatment following LPS exposure also reduced renal tubular cell apoptosis and attenuated renal expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, two biomarkers of tubular injury. Moreover, LPS exposure resulted in increased expression of BAX and cleaved caspase-3 and decreased expression of Bcl-2 and bone morphogenetic protein-7 in vivo and in vitro; TMP195 treatment reversed these responses. Finally, TMP195 inhibited LPS-induced upregulation of multiple proinflammatory cytokines/chemokines, including intercellular adhesion molecule-1, monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-1β, and accumulation of inflammatory cells in the injured kidney. Collectively, these data indicate that TMP195 has a powerful renoprotective effect in SA-AKI by mitigating renal tubular cell apoptosis and inflammation and suggest that targeting class IIa HDACs might be a novel therapeutic strategy for the treatment of SA-AKI that avoids the unintended adverse effects of a pan-HDAC inhibitor.
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http://dx.doi.org/10.1152/ajprenal.00405.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792695PMC
December 2020

Elevated expression of HDAC6 in clinical peritoneal dialysis patients and its pathogenic role on peritoneal angiogenesis.

Ren Fail 2020 Nov;42(1):890-901

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Peritoneal dialysis (PD) is an important renal replacement therapy for end-stage renal disease (ESRD) patients. However, its complications, such as peritoneal fibrosis (PF) and angiogenesis can cause ultrafiltration failure and PD termination. Histone deacetylase 6 (HDAC6) has been demonstrated to be involved in PF. However, its underlying role in peritoneal angiogenesis is still unknown and clinical value needs to be explored. In this study, we analyzed the expression of HDAC6 in the peritoneum from patients with non-PD and PD-related peritonitis and dialysis effluent from stable PD patients. Our study revealed that HDAC6 expressed highly in the peritoneum with peritonitis and co-stained with α-smooth muscle actin (α-SMA), a biomarker of the myofibroblast. And the level of HDAC6 in the dialysate increased with time and positively correlated with transforming growth factor-β1 (TGF-β1), interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), and negatively with cancer antigen 125 (CA125). , blockading HDAC6 with a selective inhibitor tubastatin A (TA) or silencing HDAC6 with a small interfering RNA (siRNA) prominently decreased IL-6-stimulated VEGF expression in cultured human peritoneal mesothelial cells (HPMCs), and inhibited proliferation and vasoformation of human umbilical vein endothelial cells (HUVECs). TA or HDAC6 siRNA also suppressed the expression of Wnt1, β-catenin, and the phosphorylation of STAT3 in IL-6-treated HPMCs. In summary, HDAC6 inhibition protects against PD-induced angiogenesis through suppression of IL-6/STAT3 and Wnt1/β-catenin signaling pathway, subsequently reducing the VEGF production and angiogenesis. It could become a new therapeutic target or forecast biomarker for PF, inflammation, and angiogenesis in the future.
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http://dx.doi.org/10.1080/0886022X.2020.1811119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472510PMC
November 2020

The role of protein arginine methyltransferases in kidney diseases.

Clin Sci (Lond) 2020 08;134(15):2037-2051

Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, U.S.A.

The methylation of arginine residues by protein arginine methyltransferases (PRMTs) is a crucial post-translational modification for many biological processes, including DNA repair, RNA processing, and transduction of intra- and extracellular signaling. Previous studies have reported that PRMTs are extensively involved in various pathologic states, including cancer, inflammation, and oxidative stress reaction. However, the role of PRMTs has not been well described in kidney diseases. Recent studies have shown that aberrant function of PRMTs and its metabolic products-symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA)-are involved in several renal pathological processes, including renal fibrosis, acute kidney injury (AKI), diabetic nephropathy (DN), hypertension, graft rejection and renal tumors. We aim in this review to elucidate the possible roles of PRMTs in normal renal function and various kidney diseases.
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http://dx.doi.org/10.1042/CS20200680DOI Listing
August 2020

Peritoneal fibrosis and epigenetic modulation.

Perit Dial Int 2021 03 14;41(2):168-178. Epub 2020 Jul 14.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China.

Peritoneal dialysis (PD) is an effective treatment for patients with end-stage renal disease. However, peritoneal fibrosis (PF) is a common complication that ultimately leads to ultrafiltration failure and discontinuation of PD after long-term PD therapy. There is currently no effective therapy to prevent or delay this pathologic process. Recent studies have reported epigenetic modifications involved in PF, and accumulating evidence suggests that epigenetic therapies may have the potential to prevent and treat PF clinically. The major epigenetic modifications in PF include DNA methylation, histone modification, and noncoding RNAs. The mechanisms of epigenetic regulation in PF are complex, predominantly involving modification of signaling molecules, transcriptional factors, and genes. This review will describe the mechanisms of epigenetic modulation in PF and discuss the possibility of targeting them to prevent and treat this complication.
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http://dx.doi.org/10.1177/0896860820938239DOI Listing
March 2021

Irisin Improves Myocardial Performance and Attenuates Insulin Resistance in Spontaneous Mutation ( ) Mice.

Front Pharmacol 2020 3;11:769. Epub 2020 Jun 3.

Department of Surgery, Boston University School of Medicine, Roger Williams Medical Center, Providence, RI, United States.

Background: Irisin, a newly identified peptide, is critical to regulating metabolism, thermogenesis, and reducing oxidative stresses. Our recent works demonstrated that irisin protected the heart against myocardial ischemic injury and preserved the function of mitochondria. However, whether irisin preserves myocardial performance and attenuates insulin resistance in type II diabetes remains unknown.

Objective: Effects of irisin on type II diabetes-induced cardiac dysfty unction and insulin resistance in db/db mice were studied. Methods: Homozygous db/db mice (n=5/each group) for spontaneous mutation ( ) and heterozygous (heterozygous) mice (n=5/each group) for control were used to assess for cardiac performance and impairment of insulin resistance. Homozygous and heterozygous controls received a treatment with either irisin (100 mg/kg, intraperitoneal injection, every other day) or vehicle control (PBS) for 4 weeks at 16 weeks of age. Insulin tolerance test and glucose tolerance test were employed to determine insulin resistance in mice. Cardiac function was assessed by echocardiography. Metabolic features including hyperglycemia and body growth were also examined. Immunohistochemical analysis was employed to determine myocardial hypertrophy and interstitial fibrosis. Immunoblots were employed to determine the signaling pathway associated with irisin treatment.

Results: Homozygous db/db mice developed an impairment in insulin sensitivity as indicated by Insulin tolerance test (ITT), glucose tolerance test (GTT) (p<0.05 vs non-irisin treatment), hyperglycemia (p<0.05 vs heterozygous control), and hyperinsulinemia (serum insulin: 0.81 ± 0.065 ng/ml in heterozygous control vs. 8.33 ± 0.69 ng/ml in homozygous db/db control, p<0.0001), which were attenuated by the administration of irisin (serum insulin 8.32 ± 0.68 ng/ml in homozygous db/db control vs 6.56 ± 0.38 ng/ml in homozygous db/db irisin treatment, p<0.0001). Furthermore, as compared to heterozygous control, db/db mice manifested a depression in cardiac performance [ejection fraction (EF): 91.9% ± 0.44 in heterozygous control vs 79.1% ± 2.0 in homozygous db/db control, p< 0.001] in associated myocardial remodeling (cardiac fibrosis 1.89% ± 0.09 in heterozygous control vs. 5.39% ± 0.22 in homozygous db/db control, p<0.001). Notably, the depression of cardiac function in EF (79.2% ± 2.0 homozygous db/db control vs. 88.6% ± 1.9 in homozygous db/db + irisin, p<0.01) and fractional shortening (FS) (42.2% ± 1.8 in homozygous db/db control vs. 53.2% ± 2.7 in homozygous db/db+irisin, p<0.01) and remodeling were markedly attenuated by the administration of irisin. Western blotting shows that irisin treatment prevented an approximate two-fold decrease in p38 phosphorylation and increase in histone deacetylase 4 (HDAC4) in the homozygous db/db myocardium (p<0.05 vs homozygous db/db control).

Conclusion: Irisin preserves myocardial performance and insulin resistance in db/db mice, which is related to p38 phosphorylation and HDAC reduction.
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http://dx.doi.org/10.3389/fphar.2020.00769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283381PMC
June 2020

Delayed treatment with an autophagy inhibitor 3-MA alleviates the progression of hyperuricemic nephropathy.

Cell Death Dis 2020 06 17;11(6):467. Epub 2020 Jun 17.

Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

Autophagy is a cell self-renewal process that relies on the degradation of the cytoplasmic proteins or organelles of lysosomes and is associated with development of numerous diseases. However, the therapeutic effect of autophagy inhibition on hyperuricemic nephropathy (HN) and the underlying mechanisms are still unknown. Here, we investigated the effect of delayed treatment with 3-methyladenine (3-MA), a specific autophagy inhibitor, on the development of HN in a rat model. Administration of 3-MA at 21 days following after uric acid injury protected kidney from hyperuricemic-related injuries, as demonstrated by improving renal dysfunction and architecture damage, blocking Beclin-1 and LC3II/I and decreasing the number of autophagic vacuoles. Late treatment with 3-MA was also effective in attenuating renal fibrosis as evidenced by reducing ECM protein deposition, blocking epithelial-to-mesenchymal transition (EMT) and decreasing the number of renal epithelial cells arrested at the G2/M phase of cell cycle. Injury to the kidney resulted in increased expression of TGFβ receptor I, and phosphorylation of Smad3, 3-MA significantly abrogated all these responses. Moreover, inhibition of autophagy suppressed mitochondrial fission, downregulated the expression of Dynamin-related protein 1 (Drp-1), Cofilin and F-actin, and alleviated cell apoptosis. Finally, 3-MA effectively blocked STAT3 and NF-κB phosphorylation and suppressed infiltration of macrophages and lymphocytes as well as release of multiple profibrogenic cytokines/chemokines in the injured kidney. Taken together, these findings indicate that hyperuricemia-induced autophagy is critically involved in the activation of renal fibroblasts, EMT, mitochondrial fission and apoptosis of tubular epithelial cells and development of renal fibrosis. Thus, this study provides evidence for autophagy inhibitors as the treatment of HN patients.
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http://dx.doi.org/10.1038/s41419-020-2673-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298642PMC
June 2020

Identification of histone deacetylase 8 as a novel therapeutic target for renal fibrosis.

FASEB J 2020 06 12;34(6):7295-7310. Epub 2020 Apr 12.

Department of Medicine, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, RI, USA.

Histone deacetylases (HDACs) have been shown to alleviate renal fibrosis, however, the role of individual HDAC isoforms in this process is poorly understood. In this study, we examined the role of HDAC8 in the development of renal fibrosis and partial epithelial-mesenchymal transitions (EMT). In a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), HDAC8 was primarily expressed in renal tubular epithelial cells and time-dependently upregulated. This occurred in parallel with the deacetylation of cortactin, a nonhistone substrate of HDAC8, and increased expression of three fibrotic markers: α-smooth muscle actin, collagen 1, and fibronectin. Administration of PCI34051, a highly selective inhibitor of HDAC8, restored acetylation of contactin and reduced expression of those proteins. PCI34051 treatment also reduced the number of renal tubular epithelial cells arrested at the G2/M phase of the cell cycle and suppressed phosphorylation of Smad3, STAT3, β-catenin, and expression of Snail after ureteral obstruction. In contrast, HDAC8 inhibition reversed UUO-induced downregulation of BMP7 and Klotho, two renoprotective proteins. In cultured murine proximal tubular cells, treatment with PCI34051 or specific HDAC8 siRNA was also effective in inhibiting transforming growth factor β1 (TGFβ1)-induced deacetylation of contactin, EMT, phosphorylation of Smad3, STAT3, and β-catenin, upregulation of Snail, and downregulation of BMP7 and Klotho. Collectively, these results suggest that HDAC8 activation is required for the EMT and renal fibrogenesis by activation of multiple profibrotic signaling and transcription factors, and suppression of antifibrotic proteins. Therefore, targeting HDAC8 may be novel therapeutic approach for treatment of renal fibrosis.
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http://dx.doi.org/10.1096/fj.201903254RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445474PMC
June 2020
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