Targeting Neuromedin S as a novel therapy for advanced diabetic kidney disease
Currently the management of diabetic kidney disease focuses on the treatment of hyperglycemia and high blood pressure. Clinical trials intensifying the management of glycemia or maximal treatment of high blood pressure have not decreased the risk of death or end-stage renal disease (ESRD), suggesting that other mechanism(s) may be involved in the pathogenesis of diabetic kidney disease and that new therapeutic agents are urgently needed. In a proteomic and microarray screen, we identified neuromedin s (NMS) – a poorly characterised neuropeptide - as a major factor secreted by injured endothelial cells that can directly cause podocyte injury and enhance TGF-ß1-induced activation of renal fibroblasts in vitro. Our subsequent studies identified marked up-regulation of NMS production by endothelial cells in human and experimental diabetic kidney disease. Furthermore, our exciting preliminary data shows that NMS deficient (NMS-/-) mice are significantly protected from renal interstitial fibrosis in the unilateral ureteral obstruction (UUO) model - the first study to identify a role for NMS in tissue fibrosis. In addition, we have generated a neutralising mouse anti-mouse NMS antibody (a-NMS Ab) for use as a pharmacologic NMS inhibitor. Administration of a-NMS Ab significantly decreases renal interstitial fibrosis in UUO. NMS is strongly upregulated in renal endothelial cells in advanced diabetic renal disease in a type II diabetes model, eNOS-/-db/db mice. Based on our compelling preliminary data, we hypothesis that NMS is a novel mediator of progressive diabetic kidney disease through inducing podocyte damage and promoting renal fibrosis. We will test whether administration of anti-NMS Ab will retard or even reverse the development and progression of diabetic nephropathy in type 2 diabetes model, eNOS-/-db/db mice. In addition, the direct effect of NMS on podocytes and mesangial cells will be investigated in vitro. This project will provide a major advance in our understanding of the role of NMS in the induction and progression of diabetic renal disease. The positive results will have clear translational potential as a new therapy for diabetic nephropathy, as well as for other diabetic complications.

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