Absence of miR-146a in podocytes increases risk of diabetic glomerulopathy via upregulation of erbb4 and notch-1.
Lee HW, Khan SQ, Khaliqdina S, Altintas MM, Grahammer F, Zhao JL, Koh KH, Tardi NJ, Faridi MH, Geraghty T, Cimbaluk DJ, Susztak K, Moita LF, Baltimore D, Tharaux PL, Huber TB, Kretzler M, Bitzer M, Reiser J, Gupta V.
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.
