New Mechanisms in the Pathogenesis of Diabetic Nephropathy

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DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is one of the major complications of diabetes. It accounts for almost half of all patients with end stage renal disease needing dialysis and is therefore a major health care problem. However the basic underlying molecular mechanisms are not very clear. Transforming growth factor-beta (TGF-¿) has been implicated in the pathogenesis of DN. It is induced under diabetic conditions and can increase the expression of extracellular matrix proteins such as collagen in mesangial cells, leading to glomerular dysfunction. In a gene array screen, we identified two new gene targets of TGF-¿ in mesangial cells. One of these was noted to be a key transcription factor that could modulate the expression of collagen. Interestingly, we uncovered a novel connection between this family of transcription factors and two members of a new family of small non-coding RNAs called micro-RNAs (miRs). Recent evidence shows that miRs play important roles in gene regulation since they can suppress translation of target genes by binding to their mRNAs. Although several targets of miRs have been predicted, much needs to be done to determine their biological and disease relevance. Furthermore, nothing is known in the context of diabetic complications including DN and we propose to explore our innovative idea in this context. We discovered that our newly identified transcription factor targets of TGF-¿ that are involved in collagen regulation, are also targets of two miRs that are expressed in the kidney. Furthermore, interestingly, these transcription factors in turn can inhibit the expression of these miRs, thereby suggesting a novel cross talk and feed forward loop that can contribute to mesangial cell and glomerular matrix expression. We therefore put forward the innovative hypothesis that DN is a result of aberrant expression and actions of these miRs in the kidney and mesangial cells in response to TGF-¿. Specific Aims 1 and 2 will examine gain and loss of function approaches as well as transcriptomic mechanisms to evaluate the involvement of the new TGF-¿ targets and two miRs in mouse mesangial cell gene expression. Specific Aim 3 will then test the in vivo functional relevance in a mouse model of DN by examining the renal cortical expression of miRs and target genes and the effects of downregulation of a key miR. Overall, we will explore new related mechanisms and players in the development of DN. This work could break new ground and have a major impact in the field of renal research as well as lay the foundation for deciphering the biological functions of these elusive factors in the kidney. They could also pave the way for novel new therapies for various complications of diabetes including nephropathy.