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Absence of miR-146a in podocytes increases risk of diabetic glomerulopathy via upregulation of erbb4 and notch-1

Lee, Ha Won and Khan, Samia Q. and Khaliqdina, Shehryar and Altintas, Mehmet M. and Grahammer, Florian and Zhao, Jimmy L. and Koh, Kwihey and Tardi, Nicholas J. and Faridi, Mohd Hafeez and Geraghty, Terese and Cimbaluk, David J. and Susztak, Katalin and Moita, Luis F. and Baltimore, David and Tharaux, Pierre-Louis and Huber, Tobias B. and Kretzler, Matthias and Bitzer, Markus and Reiser, Jochen and Gupta, Vineet (2017) Absence of miR-146a in podocytes increases risk of diabetic glomerulopathy via upregulation of erbb4 and notch-1. Journal of Biological Chemistry, 292 (2). pp. 732-747. ISSN 0021-9258. PMCID PMC5241746. doi:10.1074/jbc.M116.753822.

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Podocyte injury is an early event in diabetic kidney disease and is a hallmark of glomerulopathy. MicroRNA-146a (miR-146a) is highly expressed in many cell types under homeostatic conditions, and plays an important anti-inflammatory role in myeloid cells. However, its role in podocytes is unclear. Here, we show that miR-146a expression levels decrease in the glomeruli of patients with type 2 diabetes (T2D), which correlates with increased albuminuria and glomerular damage. MiR-146a levels are also significantly reduced in the glomeruli of albuminuric BTBR ob/ob mice, indicating its significant role in maintaining podocyte health. miR-146a-deficient mice (miR-146a-/-) showed accelerated development of glomerulopathy and albuminuria upon streptozotocin (STZ)-induced hyperglycemia. The miR-146a targets, Notch-1 and ErbB4, were also significantly upregulated in the glomeruli of diabetic patients and mice, suggesting induction of the downstream TGFβ-signaling. Treatment with a pan-ErbB kinase inhibitor erlotinib with nanomolar activity against ErbB4 significantly suppressed diabetic glomerular injury and albuminuria in both WT and miR-146a-/- animals. Treatment of podocytes in vitro with TGF-β1 resulted in increased expression of Notch-1, ErbB4, pErbB4 and pEGFR, the heterodimerization partner of ErbB4, suggesting increased ErbB4/EGFR signaling. TGF-β1 also increased levels of inflammatory cytokine MCP-1 and MCP-1 induced protein-1 (MCPIP1), a suppressor of miR-146a, suggesting an autocrine loop. Inhibition of ErbB4/EGFR with erlotinib co-treatment of podocytes suppressed this signaling. Our findings suggest a novel role for miR-146a in protecting against diabetic glomerulopathy and podocyte injury. They also point to Erbb4/EGFR as a novel, druggable target for therapeutic intervention, especially since several pan-ErbB inhibitors are clinically available.

Item Type:Article
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URLURL TypeDescription Data CentralArticle
Baltimore, David0000-0001-8723-8190
Gupta, Vineet0000-0001-6987-2550
Additional Information:© 2016 The American Society for Biochemistry and Molecular Biology. Received August 16, 2016; Accepted December 2, 2016. We thank Hatem Elshabrawy, Saravana Kanagavelu, Steve Mangos, Andrew Armstrong, Isabel Fernandez, Prachal Bhargava, Dony Maiguel, Tristan Hays and Alex Braley for generous technical help with the podocyte cell-based assays, animal husbandry and for helpful discussions. Author Contributions: HWL, SQK, SJK, MHF designed and performed in vitro and in vivo experiments with erlotinib and analyzed data; HWL, MMA, TG and KHK performed western blots, PCR and qPCR and analyzed data; SQK, SJK, FG, KS, P-LT and TBH designed, performed and analyzed immunofluorescence studies; NJT performed TEM studies; DJC helped with histopathology; MHF, SJK, JLZ, LFM, DB and TBH helped design in vivo assays using miR-146a KO animals; MK, MB, JR and VG analyzed human data; VG designed and supervised the studies and HWL, SQK and VG co-wrote the paper. All authors reviewed and approved the final version of the manuscript. This work was supported in part by NIH Grants R01DK084195, R01HL109582 (to V.G.) and R01DK106512 and R01DK107984 (to V.G. and J.R.), the Nephcure Foundation and with resources from the Rush University Medical Center. Conflict of Interest: V.G. and J.R. are inventors on pending patent applications related to this study. These authors and the Rush University Medical Center have the potential for financial benefit from their future commercialization.
Funding AgencyGrant Number
Nephcure FoundationUNSPECIFIED
Subject Keywords:Podocytes, microRNA, miR-146a, diabetic glomerulopathy
Issue or Number:2
PubMed Central ID:PMC5241746
Record Number:CaltechAUTHORS:20161212-110038485
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Official Citation:Ha Won Lee, Samia Q. Khan, Shehryar Khaliqdina, Mehmet M. Altintas, Florian Grahammer, Jimmy L. Zhao, Kwi Hye Koh, Nicholas J. Tardi, Mohd. Hafeez Faridi, Terese Geraghty, David J. Cimbaluk, Katalin Susztak, Luis F. Moita, David Baltimore, Pierre-Louis Tharaux, Tobias B. Huber, Matthias Kretzler, Markus Bitzer, Jochen Reiser, and Vineet Gupta Absence of miR-146a in Podocytes Increases Risk of Diabetic Glomerulopathy via Up-regulation of ErbB4 and Notch-1 J. Biol. Chem. 2017 292: 732-. doi:10.1074/jbc.M116.753822
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:72721
Deposited By: Tony Diaz
Deposited On:12 Dec 2016 19:19
Last Modified:07 Apr 2022 16:17

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