Molecular Mechanisms of Diabetic Nephropathy:Dickkopf-1 Signaling Components and Renal Fibrosis

Diabetic nephropathy is a leading cause of end-stage renal disease in Taiwan. Intense fibrotic matrix accumulation in renal glomeruli that impairs renal function contributes to the pathogenesis of diabetic nephropathy [1]. We have found that disturbed Wnt/b-catenin signaling participated in high glucose-mediated renal cell apoptosis and renal dysfunction [2,3]. Dickkopf-1 (DKK1), a Wnt inhibitor, reportedly controls remodeling of various tissue types. Modulations of Wnt inhibitor action are creatively strategies beneficial for alleviates tissue deterioration [4-6]. The biological significance of DKK1 in high glucose-dysregulated renal tissue homeostasis has not been tested. We preliminarily found that high glucose induced fibrosis-promoting factor TGF-b1 and fibronectin associated with upregulated DKK1 and receptor Kremen2 expression of renal mesangial cells. Interestingly, in vivo knock down of DKK1 alleviated the deleterious actions of high glucose on renal tissue in diabetic rats [7]. We hypothesize that DKK1 is an emerging renal-deleterious factor that accelerates renal cell apoptosis and fibrosis in high glucose-stressed renal tissue microenvironments. Modulation of DKK1 signaling may be an innovative strategy for preventing diabetic nephropathy. The rationale and specific aims of the current project are outlined below: Specific aim 1: Employing diabetic animal models, we plan to specifically validate the expression of DKK1 signaling components in diabetic kidney tissues by advanced laser capture micro-dissection and functional genomic array technology. Specific aim 2: We attempt to delineate pathologic role of DKK1 signaling components in high glucose-induced fibrosis and apoptosis of renal cells. We also investigate which signaling transduction responsible for high glucose induction of DKK1 expression and DKK1-mediated renal cell dysfunction. Specific aim 3: We intend to explore strategies for in vivo knock down of DKK1 signaling components and attenuate diabetes-mediated renal dysfunction. We also investigate proteome-wide mechanism underlying DKK1 modulation of diabetes-induced renal tissue remodeling. Anticipated results: We anticipate that control of DKK1 signaling in renal tissue will be an innovative potential for preventing renal tissue against high glucose stress.

Project ID:PG9912-0278
External Project ID:NHRI-EX100-9942SI