Identifying genomic pathways associated with fibrosis in diabetic nephropathy
Diabetic nephropathy (DN) is the most common cause of end-stage renal disease in the US. Our long term goal is to define mechanisms responsible for progression and reversal of DN, and to establish a basis for therapeutics to reverse DN. Fibrosis in the glomerulus and tubulointerstitium is a major contributor to the decline of renal function in DN. Although traditionally fibrosis in DN has been thought to be irreversible there are indications that resolution of renal fibrotic lesions is possible. Importantly there is evidence that regression of fibrosis is sufficient to improve renal function. Still, there are no treatments specifically indicated to target reversal of renal fibrosis. The Alpers lab has shown that the BTBR mouse strain with the ob/ob leptin-deficiency mutation develops Type 2 diabetes (T2D) and severe DN. We present evidence that full reversibility of DN can be achieved in this model with leptin replacement. Several kinase cascades have been implicated in DN (e.g. ERKs, PKCs, Jaks). Chromatin immunoprecipitation (ChIP) assays revealed that kinases/phosphatases/receptors previously implicated in fibrogenesis can be found at genes involved in fibrogenesis. Thus, our overall hypothesis is that characterization of these signaling factors at fibrogenic genes during DN progression and regression can identify new targets for pharmacologic inhibitors to reverse fibrosis in DN. We have developed a high-throughput multiplex chromatin immunoprecipitation platform, Matrix ChIP-MeDIP, and computational tools that taken together for the first time make it possible to simultaneously study nuclear signaling cascades immediately upstream of chromatin/transcriptional events. The Specific Aim of this pilot project is to demonstrate the feasibility of defining differences in signaling enzymes/receptors at fibrogenesis-related genes in kidneys from wild-type BTBR compared to the T2D BTBR ob/ob mice. The proposed transforming strategy to characterize signaling pathway alterations at fibrogenic genes specific to progression and regression of diabetes complications is the first of its kind to identify and then test novel therapeutic targets in the nucleus for pharmacologic inhibition to prevent and reverse renal fibrosis in DN.

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