NOD2 promotes renal injury by exacerbation of inflammation and podocyteinsulin resistance in diabetic nephropathy

Pengchao Du1, Baoxia Fan1, Huirong Han1, Junhui Zhen2, Jin Shang1, Xiaojie Wang1, Xiang Li1,Weichen Shi1, Wei Tang3, Chanchan Bao4, Ziying Wang1, Yan Zhang1, Bin Zhang1, Xinbing Wei1, and Fan Yi1*

1Department of Pharmacology, Shandong University School of Medicine, Jinan, China, 250012

2Department of Pathology, Shandong University School of Medicine, Jinan, China, 250012

3Department of Pathogenic Biology, Shandong University School of Medicine, Jinan, China,

250012

4The Microscopy Characterization Platform, Shandong University, Jinan, China, 250012

Running title: NOD2 and diabetic nephropathy

Words count: 3998

*

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Reprint Requests to: Fan Yi, Ph.D

Professor

Department of Pharmacology

Shandong University School of Medicine

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E-mail: fanyi@sdu.edu.cn

Abstract

An increasing number of clinical and animal model studies have implicated that the activation of innate immune system and inflammatory mechanisms are of importance in the pathogenesis of diabetic nephropathy (DN). NOD2, one member of the NOD-like (NLR) receptor family, plays an important role in innate immune response. This study was to explore the contribution of NOD2 to the pathogenesis of DN and hypothesized that NOD2 was associated with inflammation and insulin resistance in DN. We found the upregulation of NOD2 in the kidney from human DN biopsies and HFD/STZ-induced diabetic mice. Further studies revealed that NOD2 deficiency ameliorated renal injury in diabetic mice. In vitro, NOD2 induced proinflammatory response and impaired insulin signaling and insulin-induced glucose uptake in podocytes. Moreover, considering that nephrin is critical for insulin action, we detected nephrin expression in hyperglycaemia. Blockade of hyperglycaemia-reduced nephrin expression was observed in NOD2^-/- diabetic mice and nephrin expression in the podocyte was dependently regulated by NOD2 activation, gene silencing of NOD2 attenuated high glucose-induced nephrin downregulation, indicating the essential role of NOD2 in mediating hyperglycaemia-induced podocytes dysfunction. These findings for the first time demonstrate that NOD2 is one of critical components of a signal transduction pathway that links renal injury to inflammation and podocyte insulin resistance in DN.

Key words:

NLR family, insulin resistance, immune homeostasis, diabetic nephropathy, podocytes