| Authors |
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
|
| Submitted By |
Markus Bitzer on 1/16/2018 |
| Status |
Published |
| Journal |
The Journal of biological chemistry |
| Year |
2017 |
| Date Published |
1/1/2017 |
| Volume : Pages |
292 : 732 - 747 |
| PubMed Reference |
27913625 |
| 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 TGFß 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-ß1 resulted in increased
expression of Notch-1, ErbB4, pErbB4, and pEGFR, the heterodimerization partner
of ErbB4, suggesting increased ErbB4/EGFR signaling. TGF-ß1 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.
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