Publications by authors named "John Cijiang He"

119 Publications

Inhibition of HIPK2 Alleviates Thoracic Aortic Disease in Mice With Progressively Severe Marfan Syndrome.

Arterioscler Thromb Vasc Biol 2021 Jul 29:ATVBAHA121316464. Epub 2021 Jul 29.

Department of Pharmacological Sciences, Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York. (C.I.C., J.H., B.C., T.H., R.I., F.R.).

Objective: Despite considerable research, the goal of finding nonsurgical remedies against thoracic aortic aneurysm and acute aortic dissection remains elusive. We sought to identify a novel aortic protein kinase that can be pharmacologically targeted to mitigate aneurysmal disease in a well-established mouse model of early-onset progressively severe Marfan syndrome (MFS). Approach and Results: Computational analyses of transcriptomic data derived from the ascending aorta of MFS mice predicted a probable association between thoracic aortic aneurysm and acute aortic dissection development and the multifunctional, stress-activated HIPK2 (homeodomain-interacting protein kinase 2). Consistent with this prediction, gene inactivation significantly extended the survival of MFS mice by slowing aneurysm growth and delaying transmural rupture. HIPK2 also ranked among the top predicted protein kinases in computational analyses of genes differentially expressed in the dilated aorta of 3 MFS patients, which strengthened the clinical relevance of the experimental finding. Additional in silico analyses of the human and mouse data sets identified the TGF (transforming growth factor)-β/Smad3 signaling pathway as a potential target of HIPK2 in the MFS aorta. Chronic treatment of MFS mice with an allosteric inhibitor of HIPK2-mediated stimulation of Smad3 signaling validated this prediction by mitigating thoracic aortic aneurysm and acute aortic dissection pathology and partially improving aortic material stiffness.

Conclusions: HIPK2 is a previously unrecognized determinant of aneurysmal disease and an attractive new target for antithoracic aortic aneurysm and acute aortic dissection multidrug therapy.
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http://dx.doi.org/10.1161/ATVBAHA.121.316464DOI Listing
July 2021

Global transcriptomic changes in glomerular endothelial cells in mice with podocyte depletion and glomerulosclerosis.

Cell Death Dis 2021 Jul 9;12(7):687. Epub 2021 Jul 9.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Podocytes are a key component of the glomerular filtration barrier, and its dysfunction and eventual loss drive glomerular disease progression. Recent research has demonstrated the importance of podocyte cross-talk with other glomerular cells, such as glomerular endothelial cells (GECs), in both glomerular homeostasis and in disease settings. However, how GECs are affected globally by podocyte injury and loss in disease settings remains unclear. Therefore, to characterize the molecular changes occurring in GECs in response to the podocyte loss, we performed the transcriptomic profiling of isolated GECs after diphtheria toxin (DT)-mediated podocyte depletion in transgenic mice with podocyte-specific human DT receptor and endothelial-specific enhanced yellow fluorescent protein (EYFP) expression. DT administration led to nearly 40% of podocyte loss with the development of glomerulosclerosis. Differential gene expression analysis of isolated GECs in the diseased mice showed significant changes in pathways related to cell adhesion and actin cytoskeleton, proliferation, and angiogenesis, as well as apoptosis and cell death. However, quantification of EYFP + GECs indicated that there was a reduction in GECs in the diseased mice, suggesting that despite the ongoing proliferation, the concomitant injury and the activation of cell death program results in their overall net loss. The upstream regulator analysis strongly indicated the involvement of p53, TGF-β1, and TNF-α as key mediators of the molecular changes occurring in GECs in the diseased mice. Our findings demonstrate significant molecular changes in GECs as a secondary consequence of podocyte loss and provide a valuable resource for further in-depth analysis of potential glomerular cross-talk mediators.
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http://dx.doi.org/10.1038/s41419-021-03951-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270962PMC
July 2021

Tackling Dialysis Burden around the World: A Global Challenge.

Kidney Dis (Basel) 2021 May 29;7(3):167-175. Epub 2021 Apr 29.

National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.

CKD is a global problem that causes significant burden to the healthcare system and the economy in addition to its impact on morbidity and mortality of patients. Around the world, in both developing and developed economies, the nephrologists and governments face the challenges of the need to provide a quality and cost-effective kidney replacement therapy for CKD patients when their kidneys fail. In December 2019, the 3rd International Congress of Chinese Nephrologists was held in Nanjing, China, and in the meeting, a symposium and roundtable discussion on how to deal with this CKD burden was held with opinion leaders from countries and regions around the world, including Australia, Canada, China, Hong Kong, Singapore, Taiwan, the UK, and the USA. The participants concluded that an integrated approach with early detection of CKD, prompt treatment to slow down progression, promotion of home-based dialysis therapy like peritoneal dialysis and home HD, together with promotion of kidney transplantation, are possible effective ways to combat this ongoing worldwide challenge.
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http://dx.doi.org/10.1159/000515541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215964PMC
May 2021

A Novel Mechanism of Regulation for Exosome Secretion in the Diabetic Kidney.

Diabetes 2021 Jul 21;70(7):1440-1442. Epub 2021 Jun 21.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

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http://dx.doi.org/10.2337/dbi21-0015DOI Listing
July 2021

Krüppel-like factor 6-mediated loss of BCAA catabolism contributes to kidney injury in mice and humans.

Proc Natl Acad Sci U S A 2021 Jun;118(23)

Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, NY 11794;

Altered cellular metabolism in kidney proximal tubule (PT) cells plays a critical role in acute kidney injury (AKI). The transcription factor Krüppel-like factor 6 (KLF6) is rapidly and robustly induced early in the PT after AKI. We found that PT-specific knockdown ( ) is protective against AKI and kidney fibrosis in mice. Combined RNA and chromatin immunoprecipitation sequencing analysis demonstrated that expression of genes encoding branched-chain amino acid (BCAA) catabolic enzymes was preserved in mice, with KLF6 occupying the promoter region of these genes. Conversely, inducible overexpression suppressed expression of BCAA genes and exacerbated kidney injury and fibrosis in mice. In vitro injured cells overexpressing had similar decreases in BCAA catabolic gene expression and were less able to utilize BCAA. Furthermore, knockdown of , which encodes one subunit of the rate-limiting enzyme in BCAA catabolism, resulted in reduced ATP production, while treatment with BCAA catabolism enhancer BT2 increased metabolism. Analysis of kidney function, , and BCAA gene expression in human chronic kidney disease patients showed significant inverse correlations between and both kidney function and BCAA expression. Thus, targeting KLF6-mediated suppression of BCAA catabolism may serve as a key therapeutic target in AKI and kidney fibrosis.
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http://dx.doi.org/10.1073/pnas.2024414118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201852PMC
June 2021

Predictive Approaches for Acute Dialysis Requirement and Death in COVID-19.

Clin J Am Soc Nephrol 2021 May 24. Epub 2021 May 24.

The Mount Sinai Clinical Intelligence Center, Icahn School of Medicine at Mount Sinai, New York, New York

Background And Objectives: AKI treated with dialysis initiation is a common complication of coronavirus disease 2019 (COVID-19) among hospitalized patients. However, dialysis supplies and personnel are often limited.

Design, Setting, Participants, & Measurements: Using data from adult patients hospitalized with COVID-19 from five hospitals from the Mount Sinai Health System who were admitted between March 10 and December 26, 2020, we developed and validated several models (logistic regression, Least Absolute Shrinkage and Selection Operator (LASSO), random forest, and eXtreme GradientBoosting [XGBoost; with and without imputation]) for predicting treatment with dialysis or death at various time horizons (1, 3, 5, and 7 days) after hospital admission. Patients admitted to the Mount Sinai Hospital were used for internal validation, whereas the other hospitals formed part of the external validation cohort. Features included demographics, comorbidities, and laboratory and vital signs within 12 hours of hospital admission.

Results: A total of 6093 patients (2442 in training and 3651 in external validation) were included in the final cohort. Of the different modeling approaches used, XGBoost without imputation had the highest area under the receiver operating characteristic (AUROC) curve on internal validation (range of 0.93-0.98) and area under the precision-recall curve (AUPRC; range of 0.78-0.82) for all time points. XGBoost without imputation also had the highest test parameters on external validation (AUROC range of 0.85-0.87, and AUPRC range of 0.27-0.54) across all time windows. XGBoost without imputation outperformed all models with higher precision and recall (mean difference in AUROC of 0.04; mean difference in AUPRC of 0.15). Features of creatinine, BUN, and red cell distribution width were major drivers of the model's prediction.

Conclusions: An XGBoost model without imputation for prediction of a composite outcome of either death or dialysis in patients positive for COVID-19 had the best performance, as compared with standard and other machine learning models.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_07_09_CJN17311120.mp3.
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http://dx.doi.org/10.2215/CJN.17311120DOI Listing
May 2021

Epithelial proliferation and cell cycle dysregulation in kidney injury and disease.

Kidney Int 2021 07 6;100(1):67-78. Epub 2021 Apr 6.

Department of Medicine, Nephrology Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Renal Program, James J. Peters Veterans Affairs Medical Center, Bronx, New York, USA. Electronic address:

Various cellular insults and injury to renal epithelial cells stimulate repair mechanisms to adapt and restore the organ homeostasis. Renal tubular epithelial cells are endowed with regenerative capacity, which allows for a restoration of nephron function after acute kidney injury. However, recent evidence indicates that the repair is often incomplete, leading to maladaptive responses that promote the progression to chronic kidney disease. The dysregulated cell cycle and proliferation is also a key feature of renal tubular epithelial cells in polycystic kidney disease and HIV-associated nephropathy. Therefore, in this review, we provide an overview of cell cycle regulation and the consequences of dysregulated cell proliferation in acute kidney injury, polycystic kidney disease, and HIV-associated nephropathy. An increased understanding of these processes may help define better targets for kidney repair and combat chronic kidney disease progression.
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http://dx.doi.org/10.1016/j.kint.2021.03.024DOI Listing
July 2021

Disparate roles of retinoid acid signaling molecules in kidney disease.

Am J Physiol Renal Physiol 2021 05 1;320(5):F683-F692. Epub 2021 Mar 1.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

Retinoid acid (RA) is synthesized mainly in the liver and has multiple functions in development, cell differentiation and proliferation, and regulation of inflammation. RA has been used to treat multiple diseases, such as cancer and skin disorders. The kidney is a major organ for RA metabolism, which is altered in the diseased condition. RA is known to have renal-protective effects in multiple animal models of kidney disease. RA has been shown to ameliorate podocyte injury through induction of expression of differentiation markers and regeneration of podocytes from its progenitor cells in animal models of kidney disease. The effects of RA in podocytes are mediated mainly by activation of the cAMP/PKA pathway via RA receptor-α (RARα) and activation of its downstream transcription factor, Kruppel-like factor 15. Screening of RA signaling molecules in human kidney disease has revealed RAR responder protein 1 () as a risk gene for glomerular disease progression. RARRES1, a podocyte-specific growth arrest gene, is regulated by high doses of both RA and TNF-α. Mechanistically, RARRES1 is cleaved by matrix metalloproteinases to generate soluble RARRES1, which then induces podocyte apoptosis through interaction with intracellular RIO kinase 1. Therefore, a high dose of RA may induce podocyte toxicity through upregulation of RARRES1. Based on the current findings, to avoid potential side effects, we propose three strategies to develop future therapies of RA for glomerular disease: ) develop RARα- and Kruppel-like factor 15-specific agonists, ) use the combination of a low dose of RAR-α agonist with phosphodiesterase 4 inhibitors, and ) use a combination of RARα agonist with RARRES1 inhibitors. Retinoic acid (RA) exerts pleotropic cellular effects, including induction of cell differentiation while inhibiting proliferation and inflammation. These effects are mediated by both RA responsive element-dependent or -independent pathways. In kidneys, RA confers renoprotection by signaling through podocyte RA receptor (RAR)α and activation of cAMP/PKA/Kruppel-like factor 15 pathway to promote podocyte differentiation. Nevertheless, in kidney disease settings, RA can also promote podocyte apoptosis and loss through downstream expression of RAR responder protein 1, a recently described risk factor for glomerular disease progression. These disparate roles of RA underscore the complexity of its effects in kidney homeostasis and disease, and a need to target specific RA-mediated pathways for effective therapeutic treatments against kidney disease progression.
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http://dx.doi.org/10.1152/ajprenal.00045.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174805PMC
May 2021

Low expression of HIV genes in podocytes accelerates the progression of diabetic kidney disease in mice.

Kidney Int 2021 04 22;99(4):914-925. Epub 2020 Dec 22.

Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, USA; Renal Section, James J. Peters VAMC, Bronx, New York, USA. Electronic address:

With the widespread use combination antiretroviral therapy, there has been a dramatic decrease in HIV-associated nephropathy. However, although the patients living with HIV have low or undetectable viral load, the prevalence of chronic kidney disease (CKD) in this population remains high. Additionally, improved survival is associated with aging-related comorbidities such as diabetes and cardiovascular disease. A faster progression of CKD is associated with concurrent HIV infection and diabetes than with HIV infection or diabetes alone. To explore the potential pathogenic mechanisms that synergistically drive CKD progression by diabetes and HIV infection, we generated a new mouse model with a relatively low expression of HIV-1 proviral genes specifically in podocytes (pod-HIV mice) to better mimic the setting of kidney injury in patients living with HIV. While no apparent kidney phenotypes were observed at baseline in pod-HIV mice, the induction of mild diabetic kidney disease with streptozotocin led to significant worsening of albuminuria, glomerular injury, podocyte loss, and kidney dysfunction as compared to the mice with diabetes alone. Mechanistically, diabetes and HIV-1 synergistically increased the glomerular expression of microRNA-34a (miR-34a), thereby reducing the expression of Sirtuin-1 (SIRT1) deacetylase. These changes were also associated with increased acetylation and activation of p53 and p65 NF-κB and with enhanced expression of senescence and inflammatory markers. The treatment of diabetic pod-HIV mice with the specific Sirtuin-1 agonist BF175 significantly attenuated albuminuria and glomerulopathy. Thus, our study highlights the reduction in Sirtuin-1 as a major basis of CKD progression in diabetic patients living with HIV and suggests Sirtuin-1 agonists as a potential therapy.
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http://dx.doi.org/10.1016/j.kint.2020.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006538PMC
April 2021

Connectivity Mapping Identifies BI-2536 as a Potential Drug to Treat Diabetic Kidney Disease.

Diabetes 2021 02 16;70(2):589-602. Epub 2020 Oct 16.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

Diabetic kidney disease (DKD) remains the most common cause of kidney failure, and the treatment options are insufficient. Here, we used a connectivity mapping approach to first collect 15 gene expression signatures from 11 DKD-related published independent studies. Then, by querying the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 data set, we identified drugs and other bioactive small molecules that are predicted to reverse these gene signatures in the diabetic kidney. Among the top consensus candidates, we selected a PLK1 inhibitor (BI-2536) for further experimental validation. We found that PLK1 expression was increased in the glomeruli of both human and mouse diabetic kidneys and localized largely in mesangial cells. We also found that BI-2536 inhibited mesangial cell proliferation and extracellular matrix in vitro and ameliorated proteinuria and kidney injury in DKD mice. Further pathway analysis of the genes predicted to be reversed by the PLK1 inhibitor was of members of the TNF-α/NF-κB, JAK/STAT, and TGF-β/Smad3 pathways. In vitro, either BI-2536 treatment or knockdown of PLK1 dampened the NF-κB and Smad3 signal transduction and transcriptional activation. Together, these results suggest that the PLK1 inhibitor BI-2536 should be further investigated as a novel therapy for DKD.
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http://dx.doi.org/10.2337/db20-0580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881868PMC
February 2021

Diabetic Kidney Disease: Challenges, Advances, and Opportunities.

Kidney Dis (Basel) 2020 Jul 31;6(4):215-225. Epub 2020 Mar 31.

Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Diabetic kidney disease (DKD) is the most common cause of the end-stage renal disease (ESRD). Regardless of intensive treatments with hyperglycemic control, blood pressure control, and the use of renin-angiotensin system blockades, the prevalence of DKD remains high. Recent studies suggest that the spectrum of DKD has been changed and many progresses have been made to develop new treatments for DKD. Therefore, it is time to perform a systemic review on the new developments in the field of DKD.

Summary: Although the classic clinical presentation of DKD is characterized by a slow progression from microalbuminuria to macroalbuminuria and by a hyperfiltration at the early stage and progressive decline of renal function at the late stage, recent epidemiological studies suggest that DKD patients have a variety of clinical presentations and progression rates to ESRD. Some DKD patients have a decline in renal function without albuminuria but display prominent vascular and interstitial fibrosis on renal histology. DKD patients are more susceptible to acute kidney injury, which might contribute to the interstitial fibrosis. A large portion of type 2 diabetic patients with albuminuria could have overlapping nondiabetic glomerular disease, and therefore, kidney biopsy is required for differential diagnosis for these patients. Only a small portion of DKD patients eventually progress to end-stage renal failure. However, we do not have sensitive and specific biomarkers to identify these high-risk patients. Genetic factors that have a strong association with DKD progression have not been identified yet. A combination of circulating tumor necrosis factor receptor (TNFR)1, TNFR2, and kidney injury molecular 1 provides predictive value for DKD progression. Artificial intelligence could enhance the predictive values for DKD progression by combining the clinical parameters and biological markers. Sodium-glucose co-transporter-2 inhibitors should be added to the new standard care of DKD patients. Several promising new drugs are in clinical trials.

Key Messages: Over last years, our understanding of DKD has been much improved and new treatments to halt the progression of DKD are coming. However, better diagnostic tools, predictive markers, and treatment options are still urgently needed to help us to better manage these patients with this detrimental disease.
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http://dx.doi.org/10.1159/000506634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445658PMC
July 2020

IL-9: a novel pro-podocyte survival cytokine in FSGS.

Kidney Int 2020 09;98(3):541-543

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA. Electronic address:

Progressive focal segmental glomerulosclerosis, characterized by podocyte loss, is often refractory to treatment and leads to progressive proteinuric chronic kidney disease. Interleukin-9 (IL-9) is reported to play important roles in innate and adaptive immunity in extrarenal inflammatory diseases. By using an IL-9 knockout mouse model, Xiong et al. demonstrate IL-9 as a novel pro-podocyte survival cytokine in the adriamycin nephropathy model of focal segmental glomerulosclerosis. Sequential in vitro and in vivo data corroborate a direct protective role, rather than an immunologic role, for IL-9 on podocyte survival. This commentary highlights these novel data and discusses the necessary steps for developing IL-9 as a potential novel therapeutic for focal segmental glomerulosclerosis.
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http://dx.doi.org/10.1016/j.kint.2020.05.045DOI Listing
September 2020

Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis.

J Exp Med 2020 09;217(9)

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1β-induced podocyte injury, potentially identifying new therapeutic targets.
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http://dx.doi.org/10.1084/jem.20191699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478737PMC
September 2020

Tubular HIPK2 is a key contributor to renal fibrosis.

JCI Insight 2020 09 3;5(17). Epub 2020 Sep 3.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

We previously used global Hipk2-null mice in various models of kidney disease to demonstrate the central role of homeodomain-interacting protein kinase 2 (HIPK2) in renal fibrosis development. However, renal tubular epithelial cell-specific (RTEC-specific) HIPK2 function in renal fibrogenesis has yet to be determined. Here, we show that modulation of tubular HIPK2 expression and activity affects renal fibrosis development in vivo. The loss of HIPK2 expression in RTECs resulted in a marked diminution of renal fibrosis in unilateral ureteral obstruction (UUO) mouse models and HIV-associated nephropathy (HIVAN) mouse models, which was associated with the reduction of Smad3 activation and downstream expression of profibrotic markers. Conversely, WT HIPK2 overexpression in RTECs accentuated the extent of renal fibrosis in the setting of UUO, HIVAN, and folic acid-induced nephropathy in mice. Notably, kinase-dead HIPK2 mutant overexpression or administration of BT173, an allosteric inhibitor of HIPK2-Smad3 interaction, markedly attenuated the renal fibrosis in these mouse models of kidney disease, indicating that HIPK2 requires both the kinase activity and its interaction with Smad3 to promote TGF-β-mediated renal fibrosis. Together, these results establish an important RTEC-specific role of HIPK2 in kidney fibrosis and further substantiate the inhibition of HIPK2 as a therapeutic approach against renal fibrosis.
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http://dx.doi.org/10.1172/jci.insight.136004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526443PMC
September 2020

Role of SIRT1 in HIV-associated kidney disease.

Am J Physiol Renal Physiol 2020 08 13;319(2):F335-F344. Epub 2020 Jul 13.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

Human immunodeficiency virus (HIV) infection of kidney cells can lead to HIV-associated nephropathy (HIVAN) and aggravate the progression of other chronic kidney diseases. Thus, a better understanding of the mechanisms of HIV-induced kidney cell injury is needed for effective therapy against HIV-induced kidney disease progression. We have previously shown that the acetylation and activation of key inflammatory regulators, NF-κB p65 and STAT3, were increased in HIVAN kidneys. Here, we demonstrate the key role of sirtuin 1 (SIRT1) deacetylase in the regulation of NF-κB and STAT3 activity in HIVAN. We found that SIRT1 expression was reduced in the glomeruli of human and mouse HIVAN kidneys and that HIV-1 gene expression was associated with reduced SIRT1 expression and increased acetylation of NF-κB p65 and STAT3 in cultured podocytes. Interestingly, SIRT1 overexpression, in turn, reduced the expression of negative regulatory factor in podocytes stably expressing HIV-1 proviral genes, which was associated with inactivation of NF-κB p65 and a reduction in HIV-1 long terminal repeat promoter activity. In vivo, the administration of the small-molecule SIRT1 agonist BF175 or inducible overexpression of SIRT1 specifically in podocytes markedly attenuated albuminuria, kidney lesions, and expression of inflammatory markers in Tg26 mice. Finally, we showed that the reduction in SIRT1 expression by HIV-1 is in part mediated through miR-34a expression. Together, our data provide a new mechanism of SIRT1 regulation and its downstream effects in HIV-1-infected kidney cells and indicate that SIRT1/miR-34a are potential drug targets to treat HIV-related kidney disease.
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http://dx.doi.org/10.1152/ajprenal.00140.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473906PMC
August 2020

Soluble RARRES1 induces podocyte apoptosis to promote glomerular disease progression.

J Clin Invest 2020 10;130(10):5523-5535

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Using the Nephrotic Syndrome Study Network Consortium data set and other publicly available transcriptomic data sets, we identified retinoic acid receptor responder protein 1 (RARRES1) as a gene whose expression positively correlated with renal function decline in human glomerular disease. The glomerular expression of RARRES1, which is largely restricted to podocytes, increased in focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). TNF-α was a potent inducer of RARRES1 expression in cultured podocytes, and transcriptomic analysis showed the enrichment of cell death pathway genes with RARRES1 overexpression. The overexpression of RARRES1 indeed induced podocyte apoptosis in vitro. Notably, this effect was dependent on its cleavage in the extracellular domain, as the mutation of its cleavage site abolished the apoptotic effect. Mechanistically, the soluble RARRES1 was endocytosed and interacted with and inhibited RIO kinase 1 (RIOK1), resulting in p53 activation and podocyte apoptosis. In mice, podocyte-specific overexpression of RARRES1 resulted in marked glomerular injury and albuminuria, while the overexpression of RARRES1 cleavage mutant had no effect. Conversely, podocyte-specific knockdown of Rarres1 in mice ameliorated glomerular injury in the setting of adriamycin-induced nephropathy. Our study demonstrates an important role and the mechanism of RARRES1 in podocyte injury in glomerular disease.
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http://dx.doi.org/10.1172/JCI140155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524479PMC
October 2020

Derivation and validation of genome-wide polygenic score for urinary tract stone diagnosis.

Kidney Int 2020 11 12;98(5):1323-1330. Epub 2020 Jun 12.

The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; The BioMe Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA; The Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Renal Program, James J Peters Veterans Affairs Medical Center at Bronx, New York, New York, USA. Electronic address:

Urinary tract stones have high heritability indicating a strong genetic component. However, genome-wide association studies (GWAS) have uncovered only a few genome wide significant single nucleotide polymorphisms (SNPs). Polygenic risk scores (PRS) sum cumulative effect of many SNPs and shed light on underlying genetic architecture. Using GWAS summary statistics from 361,141 participants in the United Kingdom Biobank, we generated a PRS and determined association with stone diagnosis in 28,877 participants in the Mount Sinai BioMe Biobank. In BioMe (1,071 cases and 27,806 controls), for every standard deviation increase, we observed a significant increment in adjusted odds ratio of a factor of 1.2 (95% confidence interval 1.13-1.26). In comparison, a risk score comprised of GWAS significant SNPs was not significantly associated with diagnosis. After stratifying individuals into low and high-risk categories on clinical risk factors, there was a significant increment in adjusted odds ratio of 1.3 (1.12-1.6) in the low- and 1.2 (1.1-1.2) in the high-risk group for every standard deviation increment in PRS. In a 14,348-participant validation cohort (Penn Medicine Biobank), every standard deviation increment was associated with a significant adjusted odds ratio of 1.1 (1.03 - 1.2). Thus, a genome-wide PRS is associated with urinary tract stones overall and in the absence of known clinical risk factors and illustrates their complex polygenic architecture.
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http://dx.doi.org/10.1016/j.kint.2020.04.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606592PMC
November 2020

Acute Kidney Injury in Hospitalized Patients with COVID-19.

medRxiv 2020 May 8. Epub 2020 May 8.

Importance: Preliminary reports indicate that acute kidney injury (AKI) is common in coronavirus disease (COVID)-19 patients and is associated with worse outcomes. AKI in hospitalized COVID-19 patients in the United States is not well-described.

Objective: To provide information about frequency, outcomes and recovery associated with AKI and dialysis in hospitalized COVID-19 patients.

Design: Observational, retrospective study.

Setting: Admitted to hospital between February 27 and April 15, 2020.

Participants: Patients aged ≥18 years with laboratory confirmed COVID-19 Exposures: AKI (peak serum creatinine increase of 0.3 mg/dL or 50% above baseline). Main Outcomes and Measures: Frequency of AKI and dialysis requirement, AKI recovery, and adjusted odds ratios (aOR) with mortality. We also trained and tested a machine learning model for predicting dialysis requirement with independent validation.

Results: A total of 3,235 hospitalized patients were diagnosed with COVID-19. AKI occurred in 1406 (46%) patients overall and 280 (20%) with AKI required renal replacement therapy. The incidence of AKI (admission plus new cases) in patients admitted to the intensive care unit was 68% (553 of 815). In the entire cohort, the proportion with stages 1, 2, and 3 AKI were 35%, 20%, 45%, respectively. In those needing intensive care, the respective proportions were 20%, 17%, 63%, and 34% received acute renal replacement therapy. Independent predictors of severe AKI were chronic kidney disease, systolic blood pressure, and potassium at baseline. In-hospital mortality in patients with AKI was 41% overall and 52% in intensive care. The aOR for mortality associated with AKI was 9.6 (95% CI 7.4-12.3) overall and 20.9 (95% CI 11.7-37.3) in patients receiving intensive care. 56% of patients with AKI who were discharged alive recovered kidney function back to baseline. The area under the curve (AUC) for the machine learned predictive model using baseline features for dialysis requirement was 0.79 in a validation test.

Conclusions And Relevance: AKI is common in patients hospitalized with COVID-19, associated with worse mortality, and the majority of patients that survive do not recover kidney function. A machine-learned model using admission features had good performance for dialysis prediction and could be used for resource allocation.
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http://dx.doi.org/10.1101/2020.05.04.20090944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274245PMC
May 2020

Novel protein synthesis-breakdown complexes: TASCCed with fibrosis after G2-M arrest.

Kidney Int 2019 11;96(5):1056-1058

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, Annenberg, New York, New York, USA. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2019.04.026DOI Listing
November 2019

Arctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes.

Nat Commun 2019 10 4;10(1):4523. Epub 2019 Oct 4.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Arctigenin (ATG) is a major component of Fructus Arctii, a traditional herbal remedy that reduced proteinuria in diabetic patients. However, whether ATG specifically provides renoprotection in DKD is not known. Here we report that ATG administration is sufficient to attenuate proteinuria and podocyte injury in mouse models of diabetes. Transcriptomic analysis of diabetic mouse glomeruli showed that cell adhesion and inflammation are two key pathways affected by ATG treatment, and mass spectrometry analysis identified protein phosphatase 2 A (PP2A) as one of the top ATG-interacting proteins in renal cells. Enhanced PP2A activity by ATG reduces p65 NF-κB-mediated inflammatory response and high glucose-induced migration in cultured podocytes via interaction with Drebrin-1. Importantly, podocyte-specific Pp2a deletion in mice exacerbates DKD injury and abrogates the ATG-mediated renoprotection. Collectively, our results demonstrate a renoprotective mechanism of ATG via PP2A activation and establish PP2A as a potential target for DKD progression.
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http://dx.doi.org/10.1038/s41467-019-12433-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778111PMC
October 2019

Comparison of Kidney Transcriptomic Profiles of Early and Advanced Diabetic Nephropathy Reveals Potential New Mechanisms for Disease Progression.

Diabetes 2019 12 2;68(12):2301-2314. Epub 2019 Oct 2.

Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China

To identify the factors mediating the progression of diabetic nephropathy (DN), we performed RNA sequencing of kidney biopsy samples from patients with early DN, advanced DN, and normal kidney tissue from nephrectomy samples. A set of genes that were upregulated at early but downregulated in late DN were shown to be largely renoprotective, which included genes in the retinoic acid pathway and glucagon-like peptide 1 receptor. Another group of genes that were downregulated at early but highly upregulated in advanced DN consisted mostly of genes associated with kidney disease pathogenesis, such as those related to immune response and fibrosis. Correlation with estimated glomerular filtration rate (eGFR) identified genes in the pathways of iron transport and cell differentiation to be positively associated with eGFR, while those in the immune response and fibrosis pathways were negatively associated. Correlation with various histopathological features also identified the association with the distinct gene ontological pathways. Deconvolution analysis of the RNA sequencing data set indicated a significant increase in monocytes, fibroblasts, and myofibroblasts in advanced DN kidneys. Our study thus provides potential molecular mechanisms for DN progression and association of differential gene expression with the functional and structural changes observed in patients with early and advanced DN.
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http://dx.doi.org/10.2337/db19-0204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868471PMC
December 2019

MicroRNA-214 promotes chronic kidney disease by disrupting mitochondrial oxidative phosphorylation.

Kidney Int 2019 06 5;95(6):1389-1404. Epub 2019 Mar 5.

Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China. Electronic address:

Mitochondria are critical in determining a cell's energy homeostasis and fate, and mitochondrial dysfunction has been implicated in the pathogenesis of chronic kidney disease (CKD). We sought to identify causative mitochondrial microRNAs. A microarray screen of kidney tissue from healthy mice identified 97 microRNAs that were enriched in the mitochondrial fraction. We focused on microRNA-214-3p (miR-214) because of a very high ratio of mitochondrial to cytoplasmic expression in the kidney compared to other organs. Tubular expression of miR-214 was more abundant in kidney tissue from patients with CKD than from healthy controls, and was positively correlated with the degree of proteinuria and kidney fibrosis. Expression of miR-214 was also increased in the kidney of mouse models of CKD induced by obstruction, ischemia/reperfusion, and albumin overload. Proximal tubule-specific deletion of miR-214 attenuated apoptosis, inflammation, fibrosis, and mitochondrial damage in these CKD models. Pharmacologic inhibition of miR-214 had a similar effect in the albumin overload model of CKD. In vitro, overexpressing miR-214 in proximal tubular cell lines induced apoptosis and disrupted mitochondrial oxidative phosphorylation, while miR-214 expression was upregulated in response to a variety of insults. The mitochondrial genes mt-Nd6 and mt-Nd4l were identified as the specific targets of miR-214 in the kidney. Together, these results demonstrate a pathogenic role of miR-214 in CKD through the disruption of mitochondrial oxidative phosphorylation, and suggest the potential for miR-214 to serve as a therapeutic target and diagnostic biomarker for CKD.
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http://dx.doi.org/10.1016/j.kint.2018.12.028DOI Listing
June 2019

Role of CD8+ T cells in crescentic glomerulonephritis.

Nephrol Dial Transplant 2020 04;35(4):564-572

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Crescentic glomerulonephritis (cGN) comprises three main types according to the pathogenesis and immunofluorescence patterns: anti-glomerular basement membrane antibody cGN, vasculitis-associated cGN and post-infectious immune complex cGN. In this brief review of the immune-pathogenesis of cGN, the focus is mainly on the role of CD8+ T cells in the progression of cGN. Under control conditions, Bowman's capsule (BC) provides a protected immunological niche by preventing access of cytotoxic CD8+ T cells to Bowman's space and thereby podocytes. Even in experimental nephrotoxic nephritis, leukocytes accumulate around the glomeruli, but remain outside of BC, as long as the latter remains intact. However, when and where breaches in BC occur, the inflammatory cells can gain access to and destroy podocytes, thus converting cGN into rapidly progressive glomerulonephritis (RPGN). These conclusions also apply to human cGN, where biopsies show that loss of BC integrity is associated with RPGN and progression to end-stage kidney disease. We propose a two-hit hypothesis for the role of cytotoxic CD8+ T cells in the progression of cGN. The initial insult occurs in response to the immune complex formation or deposition, resulting in local capillary and podocyte injury (first hit). The injured podocytes release neo-epitopes, eventually causing T-cell activation and migration to the glomerulus. Upon generation of breaches in BC, macrophages and CD8+ T cells can now gain access to the glomerular space and destroy neo-epitope expressing podocytes (second hit), resulting in RPGN. While further investigation will be required to test this hypothesis, future therapeutic trials should consider targeting of CD8+ T cells in the therapy of progressive cGN.
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http://dx.doi.org/10.1093/ndt/gfz043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139212PMC
April 2020

Single-Cell RNA Profiling of Glomerular Cells Shows Dynamic Changes in Experimental Diabetic Kidney Disease.

J Am Soc Nephrol 2019 04 7;30(4):533-545. Epub 2019 Mar 7.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York;

Background: Recent single-cell RNA sequencing (scRNA-seq) analyses have offered much insight into cell-specific gene expression profiles in normal kidneys. However, in diseased kidneys, understanding of changes in specific cells, particularly glomerular cells, remains limited.

Methods: To elucidate the glomerular cell-specific gene expression changes in diabetic kidney disease, we performed scRNA-seq analysis of isolated glomerular cells from streptozotocin-induced diabetic endothelial nitric oxide synthase (eNOS)-deficient (eNOS) mice and control eNOS mice.

Results: We identified five distinct cell populations, including glomerular endothelial cells, mesangial cells, podocytes, immune cells, and tubular cells. Using scRNA-seq analysis, we confirmed the expression of glomerular cell-specific markers and also identified several new potential markers of glomerular cells. The number of immune cells was significantly higher in diabetic glomeruli compared with control glomeruli, and further cluster analysis showed that these immune cells were predominantly macrophages. Analysis of differential gene expression in endothelial and mesangial cells of diabetic and control mice showed dynamic changes in the pattern of expressed genes, many of which are known to be involved in diabetic kidney disease. Moreover, gene expression analysis showed variable responses of individual cells to diabetic injury.

Conclusions: Our findings demonstrate the ability of scRNA-seq analysis in isolated glomerular cells from diabetic and control mice to reveal dynamic changes in gene expression in diabetic kidneys, with variable responses of individual cells. Such changes, which might not be apparent in bulk transcriptomic analysis of glomerular cells, may help identify important pathophysiologic factors contributing to the progression of diabetic kidney disease.
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http://dx.doi.org/10.1681/ASN.2018090896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442341PMC
April 2019

Expression of Glutamate Receptor Subtype 3 Is Epigenetically Regulated in Podocytes under Diabetic Conditions.

Kidney Dis (Basel) 2019 Feb 26;5(1):34-42. Epub 2018 Oct 26.

Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Recent studies suggest a role of epigenetics in the pathogenesis of diabetic kidney disease. However, epigenetic changes occurring specifically in kidney cells is poorly understood.

Methods: To examine the epigenetic regulation of genes in podocytes under diabetic conditions, we performed DNA methylation and transcriptomic profiling in podocytes exposed to high glucose conditions.

Results: Comparative analysis of genes with DNA methylation changes and correspondingly altered mRNA expression identified 337 hypomethylated genes with increased mRNA expression and only 2 hypermethyated genes ( and ) with decreased mRNA expression. Glutamate ionotropic receptor AMPA type subunit 3 () belongs to the ionotropic class of glutamate receptors that mediate fast excitatory synaptic transmission in the central nervous system. As podocytes have glutamate-containing vesicles and various glutamate receptors mediate important biological effects in podocytes, we further examined expression and its function in podocytes. Real-time PCR and western blots confirmed the suppression of expression in podocytes under high glucose conditions, which were abolished in the presence of a DNA methyltransferase inhibitor. Sites of DNA hypermethylation were also confirmed by bisulfite sequencing of the promoter region. mRNA and protein expression was suppressed in diabetic kidneys of human and mouse models, and knockdown of exacerbated high glucose-induced apoptosis in cultured podocytes.

Conclusion: These results indicate that decreased expression in podocytes in diabetic condition heightens podocyte apoptosis and loss.
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http://dx.doi.org/10.1159/000492933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388444PMC
February 2019

Tyro3 is a podocyte protective factor in glomerular disease.

JCI Insight 2018 11 15;3(22). Epub 2018 Nov 15.

Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Our previous work demonstrated a protective role of protein S in early diabetic kidney disease (DKD). Protein S exerts antiinflammatory and antiapoptotic effects through the activation of TYRO3, AXL, and MER (TAM) receptors. Among the 3 TAM receptors, we showed that the biological effects of protein S were mediated largely by TYRO3 in diabetic kidneys. Our data now show that TYRO3 mRNA expression is highly enriched in human glomeruli and that TYRO3 protein is expressed in podocytes. Interestingly, glomerular TYRO3 mRNA expression increased in mild DKD but was suppressed in progressive DKD, as well as in focal segmental glomerulosclerosis (FSGS). Functionally, morpholino-mediated knockdown of tyro3 altered glomerular filtration barrier development in zebrafish larvae, and genetic ablation of Tyro3 in murine models of DKD and Adriamycin-induced nephropathy (ADRN) worsened albuminuria and glomerular injury. Conversely, the induction of TYRO3 overexpression specifically in podocytes significantly attenuated albuminuria and kidney injury in mice with DKD, ADRN, and HIV-associated nephropathy (HIVAN). Mechanistically, TYRO3 expression was suppressed by activation of TNF-α/NF-κB pathway, which may contribute to decreased TYRO3 expression in progressive DKD and FSGS, and TYRO3 signaling conferred antiapoptotic effects through the activation of AKT in podocytes. In conclusion, TYRO3 plays a critical role in maintaining normal podocyte function and may be a potential new drug target to treat glomerular diseases.
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http://dx.doi.org/10.1172/jci.insight.123482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302948PMC
November 2018

A protective role for microRNA-688 in acute kidney injury.

J Clin Invest 2018 12 12;128(12):5216-5218. Epub 2018 Nov 12.

Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Ischemia-reperfusion (I/R) sets off a devastating cascade of events, leading to cell death and possible organ failure. Treatments to limit I/R-associated damage are lacking, and the pathways that drive injury are poorly understood. In this issue of the JCI, Wei and colleagues identify microRNA-668 (miR-668) as a protective factor in acute kidney injury (AKI). miR-668 was shown to repress mitochondrial fission-associated protein MTP18, thereby inhibiting pathogenic mitochondrial fragmentation. In murine models of I/R-induced AKI, treatment with a miR-668 mimetic reduced mitochondrial fragmentation and improved renal function. Moreover, HIF-1α was shown to be required for miR-688 expression in response to I/R. Importantly, Wei et al. show miR-668 upregulation in a cohort of human patients with AKI. Together, these results identify a HIF-1α/miR-668/MTP18 axis that may have potential as a therapeutic target for AKI.
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http://dx.doi.org/10.1172/JCI124923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264641PMC
December 2018
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