Publications by authors named "Jason Ling"

7 Publications

  • Page 1 of 1

Podocyte-Specific Loss of Krüppel-Like Factor 6 Increases Mitochondrial Injury in Diabetic Kidney Disease.

Diabetes 2018 11 16;67(11):2420-2433. Epub 2018 Aug 16.

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

Mitochondrial injury is uniformly observed in several murine models as well as in individuals with diabetic kidney disease (DKD). Although emerging evidence has highlighted the role of key transcriptional regulators in mitochondrial biogenesis, little is known about the regulation of mitochondrial cytochrome c oxidase assembly in the podocyte under diabetic conditions. We recently reported a critical role of the zinc finger Krüppel-like factor 6 (KLF6) in maintaining mitochondrial function and preventing apoptosis in a proteinuric murine model. In this study, we report that podocyte-specific knockdown of increased the susceptibility to streptozotocin-induced DKD in the resistant C57BL/6 mouse strain. We observed that the loss of in podocytes reduced the expression of with resultant increased mitochondrial injury, leading to activation of the intrinsic apoptotic pathway under diabetic conditions. Conversely, mitochondrial injury and apoptosis were significantly attenuated with overexpression of in cultured human podocytes under hyperglycemic conditions. Finally, we observed a significant reduction in glomerular and podocyte-specific expression of KLF6 in human kidney biopsies with progression of DKD. Collectively, these data suggest that podocyte-specific KLF6 is critical to preventing mitochondrial injury and apoptosis under diabetic conditions.
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http://dx.doi.org/10.2337/db17-0958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198342PMC
November 2018

Krüppel-Like Factor 15 Mediates Glucocorticoid-Induced Restoration of Podocyte Differentiation Markers.

J Am Soc Nephrol 2017 Jan 10;28(1):166-184. Epub 2016 Jun 10.

Department of Pharmacology and Systems Therapeutics and.

Podocyte injury is the inciting event in primary glomerulopathies, such as minimal change disease and primary FSGS, and glucocorticoids remain the initial and often, the primary treatment of choice for these glomerulopathies. Because inflammation is not readily apparent in these diseases, understanding the direct effects of glucocorticoids on the podocyte, independent of the immunomodulatory effects, may lead to the identification of targets downstream of glucocorticoids that minimize toxicity without compromising efficacy. Several studies showed that treatment with glucocorticoids restores podocyte differentiation markers and normal ultrastructure and improves cell survival in murine podocytes. We previously determined that Krüppel-like factor 15 (KLF15), a kidney-enriched zinc finger transcription factor, is required for restoring podocyte differentiation markers in mice and human podocytes under cell stress. Here, we show that in vitro treatment with dexamethasone induced a rapid increase of KLF15 expression in human and murine podocytes and enhanced the affinity of glucocorticoid receptor binding to the promoter region of KLF15 In three independent proteinuric murine models, podocyte-specific loss of Klf15 abrogated dexamethasone-induced podocyte recovery. Furthermore, knockdown of KLF15 reduced cell survival and destabilized the actin cytoskeleton in differentiated human podocytes. Conversely, overexpression of KLF15 stabilized the actin cytoskeleton under cell stress in human podocytes. Finally, the level of KLF15 expression in the podocytes and glomeruli from human biopsy specimens correlated with glucocorticoid responsiveness in 35 patients with minimal change disease or primary FSGS. Thus, these studies identify the critical role of KLF15 in mediating the salutary effects of glucocorticoids in the podocyte.
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http://dx.doi.org/10.1681/ASN.2015060672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198263PMC
January 2017

Prominin-1 (CD133) defines both stem and non-stem cell populations in CNS development and gliomas.

PLoS One 2014 3;9(9):e106694. Epub 2014 Sep 3.

Center for Molecular Oncologic Pathology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America; Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, United States of America; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America; Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America.

Prominin-1 (CD133) is a commonly used cancer stem cell marker in central nervous system (CNS) tumors including glioblastoma (GBM). Expression of Prom1 in cancer is thought to parallel expression and function in normal stem cells. Using RNA in situ hybridization and antibody tools capable of detecting multiple isoforms of Prom1, we find evidence for two distinct Prom1 cell populations in mouse brain. Prom1 RNA is first expressed in stem/progenitor cells of the ventricular zone in embryonic brain. Conversely, in adult mouse brain Prom1 RNA is low in SVZ/SGZ stem cell zones but high in a rare but widely distributed cell population (Prom1(hi)). Lineage marker analysis reveals Prom1(hi) cells are Olig2+Sox2+ glia but Olig1/2 knockout mice lacking oligodendroglia retain Prom1(hi) cells. Bromodeoxyuridine labeling identifies Prom1(hi) as slow-dividing distributed progenitors distinct from NG2+Olig2+ oligodendrocyte progenitors. In adult human brain, PROM1 cells are rarely positive for OLIG2, but express astroglial markers GFAP and SOX2. Variability of PROM1 expression levels in human GBM and patient-derived xenografts (PDX) - from no expression to strong, uniform expression--highlights that PROM1 may not always be associated with or restricted to cancer stem cells. TCGA and PDX data show that high expression of PROM1 correlates with poor overall survival. Within proneural subclass tumors, high PROM1 expression correlates inversely with IDH1 (R132H) mutation. These findings support PROM1 as a tumor cell-intrinsic marker related to GBM survival, independent of its stem cell properties, and highlight potentially divergent roles for this protein in normal mouse and human glia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106694PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153667PMC
May 2015

The relaxin receptor (RXFP1) utilizes hydrophobic moieties on a signaling surface of its N-terminal low density lipoprotein class A module to mediate receptor activation.

J Biol Chem 2013 Sep 7;288(39):28138-51. Epub 2013 Aug 7.

From the Florey Institute of Neuroscience and Mental Health and Florey Department of Neuroscience and Mental Health.

The peptide hormone relaxin is showing potential as a treatment for acute heart failure. Although it is known that relaxin mediates its actions through the G protein-coupled receptor relaxin family peptide receptor 1 (RXFP1), little is known about the molecular mechanisms by which relaxin binding results in receptor activation. Previous studies have highlighted that the unique N-terminal low density lipoprotein class A (LDLa) module of RXFP1 is essential for receptor activation, and it has been hypothesized that this module is the true "ligand" of the receptor that directs the conformational changes necessary for G protein coupling. In this study, we confirmed that an RXFP1 receptor lacking the LDLa module binds ligand normally but cannot signal through any characterized G protein-coupled receptor signaling pathway. Furthermore, we comprehensively examined the contributions of amino acids in the LDLa module to RXFP1 activity using both gain-of-function and loss-of-function mutational analysis together with NMR structural analysis of recombinant LDLa modules. Gain-of-function studies with an inactive RXFP1 chimera containing the LDLa module of the human LDL receptor (LB2) demonstrated two key N-terminal regions of the module that were able to rescue receptor signaling. Loss-of-function mutations of residues in these regions demonstrated that Leu-7, Tyr-9, and Lys-17 all contributed to the ability of the LDLa module to drive receptor activation, and judicious amino acid substitutions suggested this involves hydrophobic interactions. Our results demonstrate that these key residues contribute to interactions driving the active receptor conformation, providing further evidence of a unique mode of G protein-coupled receptor activation.
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http://dx.doi.org/10.1074/jbc.M113.499640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784725PMC
September 2013

Dexamethasone destabilizes Nmyc to inhibit the growth of hedgehog-associated medulloblastoma.

Cancer Res 2010 Jul 8;70(13):5220-5. Epub 2010 Jun 8.

Department of Pediatrics and Neurosurgery, Howard Hughes Medical Institute and Institute for Regeneration Medicine, University of California, San Francisco, San Francisco, California 94143, USA.

Mouse studies indicate that the synthetic glucocorticoid dexamethasone (Dex) impairs the proliferation of granule neuron precursors in the cerebellum, which are transformed to medulloblastoma by activation of Sonic hedgehog (Shh) signaling. Here, we show that Dex treatment also inhibits Shh-induced tumor growth, enhancing the survival of tumor-prone transgenic mice. We found that Nmyc was specifically required in granule cells for Shh-induced tumorigenesis and that Dex acted to reduce Nmyc protein levels. Moreover, we found that Dex-induced destabilization of Nmyc is mediated by activation of glycogen synthase kinase 3beta, which targets Nmyc for proteasomal degradation. Together, our findings show that Dex antagonizes Shh signaling downstream of Smoothened in medulloblastoma.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-0554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896447PMC
July 2010

Role of RNA polymerase sigma-factor (RpoS) in induction of glutamate-dependent acid-resistance of Escherichia albertii under anaerobic conditions.

FEMS Microbiol Lett 2008 Jun 14;283(1):75-82. Epub 2008 Apr 14.

Produce Quality and Safety Laboratory, Henry A. Wallace Beltsville Agricultural Research Center, Agricultural Research Service, USDA, Beltsville, MD, USA.

Escherichia albertii is a potential enteric food-borne pathogen with poorly defined genetic and biochemical properties. Acid resistance is perceived to be an important property of enteric pathogens, enabling them to survive passage through stomach acidity so that they may colonize the mammalian gastrointestinal tract. We analyzed glutamate-dependent acid-resistance pathway (GDAR) in five E. albertii strains that have been identified so far. We observed that the strains were unable to induce GDAR under aerobic growth conditions. Mobilization of the rpoS gene restored aerobic induction of this acid-resistance pathway, indicating that all five strains may have a dysfunctional sigma-factor. On the other hand, under anaerobic growth conditions where GDAR is induced in an RpoS-independent manner (i.e. in Shigella spp. and Escherichia coli O157:H7 strains), only three out of five E. albertii strains successfully induced GDAR. The remainder of the two strains exhibited dependence on functional RpoS even under anaerobic conditions to express GDAR, a regulatory function previously considered to be redundant. The data indicate that certain E. albertii strains may have an alternate RpoS-dependent pathway for acid-resistance under anaerobic growth conditions.
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http://dx.doi.org/10.1111/j.1574-6968.2008.01153.xDOI Listing
June 2008

Sensitivity of Escherichia albertii, a potential food-borne pathogen, to food preservation treatments.

Appl Environ Microbiol 2007 Jul 27;73(13):4351-3. Epub 2007 Apr 27.

Food Technology and Safety Laboratory, USDA-ARS, ANRI, BARC-EAST, Beltsville, MD 20705, USA.

Escherichia albertii is a potential food-borne pathogen because of its documented ability to cause diarrheal disease by producing attachment and effacement lesions. Its tolerances to heat (56 degrees C), acid (pH 3.0), and pressure (500 MPa [5 min]) were evaluated and found to be significantly less than those of wild-type E. coli O157:H7.
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http://dx.doi.org/10.1128/AEM.03001-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1932773PMC
July 2007