title: Absence of miR-146a in Podocytes Increases Risk of Diabetic Glomerulopathy via Up-regulation of ErbB4 and Notch-1.
abstract: 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 up-regulated 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 monocyte chemoattractant protein-1 (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 because several pan-ErbB inhibitors are clinically available.
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Ha Won
authors.initials: HW
authors.lastname: Lee
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Samia Q
authors.initials: SQ
authors.lastname: Khan
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Shehryar
authors.initials: S
authors.lastname: Khaliqdina
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Mehmet M
authors.initials: MM
authors.lastname: Altintas
authors.affiliation: the Department of Medicine IV, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Grahammer
authors.affiliation: the Department of Medicine, New York Presbyterian/Weill Cornell Medical Center, New York, New York 10065.|the Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125.
authors.forename: Jimmy L
authors.initials: JL
authors.lastname: Zhao
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Kwi Hye
authors.initials: KH
authors.lastname: Koh
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Tardi
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Mohd Hafeez
authors.initials: MH
authors.lastname: Faridi
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Terese
authors.initials: T
authors.lastname: Geraghty
authors.affiliation: Pathology, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cimbaluk
authors.affiliation: the Department of Medicine, Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Katalin
authors.initials: K
authors.lastname: Susztak
authors.affiliation: the Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Moita
authors.affiliation: the Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125.
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
authors.affiliation: the Paris Cardiovascular Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), 75015 Paris, France and the Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris, France.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
authors.affiliation: the Department of Medicine IV, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.|the BIOSS Center for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.|the FRIAS, Freiburg Institute for Advanced Studies and ZBSA-Center for Systems Biology, Albert-Ludwigs-University, 79104 Freiburg, Germany, and.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.affiliation: the Division of Nephrology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.affiliation: the Division of Nephrology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Markus
authors.initials: M
authors.lastname: Bitzer
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.affiliation: From the Departments of Internal Medicine and vineet_gupta@rush.edu.
authors.forename: Vineet
authors.identifier: http://orcid.org/0000-0001-6987-2550
authors.initials: V
authors.lastname: Gupta
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D066247:Receptor, ErbB-4 / Q000096:biosynthesis* / Q000235:genetics; D051881:Receptor, Notch1 / Q000096:biosynthesis* / Q000235:genetics; D012260:Ribonucleases / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D000069347:Erlotinib Hydrochloride; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D012260:Ribonucleases; C541320:Zc3h12a protein, mouse
keywords: Type 1 diabetes; diabetic glomerulopathy; diabetic nephropathy; kidney; microRNA (miRNA); mir-146a; podocyte