Absence of miR-146a in Podocytes Increases Risk of Diabetic Glomerulopathy via Up-regulation of ErbB4 and Notch-1

J Biol Chem. 2017 Jan 13;292(2):732-747. doi: 10.1074/jbc.M116.753822. Epub 2016 Dec 2.


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.

Keywords: Type 1 diabetes; diabetic glomerulopathy; diabetic nephropathy; kidney; microRNA (miRNA); mir-146a; podocyte.

MeSH terms

  • Animals
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / drug therapy
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / pathology
  • Erlotinib Hydrochloride / pharmacology
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Podocytes / metabolism*
  • Podocytes / pathology
  • Receptor, ErbB-4 / biosynthesis*
  • Receptor, ErbB-4 / genetics
  • Receptor, Notch1 / biosynthesis*
  • Receptor, Notch1 / genetics
  • Ribonucleases / genetics
  • Ribonucleases / metabolism
  • Risk Factors
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Up-Regulation*


  • Ccl2 protein, mouse
  • Chemokine CCL2
  • MicroRNAs
  • Mirn146 microRNA, mouse
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • Erlotinib Hydrochloride
  • Erbb4 protein, mouse
  • Receptor, ErbB-4
  • Ribonucleases
  • Zc3h12a protein, mouse