MicroRNA-medicated Mechanisms in Diabetic Glomerular Disease
Diabetic nephropathy (DN) is a common and devastating microvascular complication in patients with Diabetes associated with cardiovascular disease and macrovascular complications and can lead to end-stage renal disease requiring dialysis or kidney transplantation. Therefore, effective renal protection is critical to reduce the rates of mortality associated with diabetes. Although our understanding of underlying mechanisms has improved and several drugs are in clinical use, treatment success remains limited, suggesting the imperative need to identify new drug targets. The recent discovery of microRNAs (miRNAs) and their cellular functions provide an opportunity to fill these critical gaps. Because miRNAs can modulate the actions of key factors involved in DN such as transforming growth factor (TGF)-beta, they could be novel targets for the treatment of DN. We have identified miRNAs that exhibit significant correlation of glomerular expression with proteinuria in patients with clinically early DN, including miR-21, miR-192 and miR-34. We determined that miR-21 inhibits expression of p53 and its downstream target miR-34 as well as podocyte apoptosis and hyperglycemia-induced glomerular injury in mice. Furthermore, we determined that miR-34 promotes podocytes apoptosis. In order to develop antisense oligonucleotides (ASO) against miRNAs as therapeutic interventions to ameliorate podocyte loss in DN, we propose to test an ASO against miR-34 in a mouse model of DN. We will determine whether inhibition of miR-34a with ASO in hyperglycemic mice ameliorates podocyte loss. In addition, mutant mice with ubiquitous and conditional deletion of miR-34 will be used as positive control. To determine that ASO against miR-34 lead to de-repression of miR-34 target genes in podocytes in mice, we propose to identify miR-34 target genes relevant in podocytes using PAR-CLIP in cultured murine podocytes. The proposed study will examine whether ASO against miR-34 ameliorate podocyte loss in DN. If successful, this study will provide evidence for the feasibility to use ASO against miRNAs in podocytes in vivo. Furthermore, this study will determine whether miR-34 is a central mediator in podocyte injury and DN, as well as candidate mechanisms of miR-34 induced injury.

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