Grant: Project Grant

Clinically evident kidney failure eventually develops in patients with type 1 (T1D) and type 2 (T2D) diabetes, and continues to progress despite receiving intensified glycemic control and renal protective drugs. Moreover, up to now, we have only a diffuse understanding of why some diabetic patients develop nephropathy whereas other patients never progress to dialysis. Elevated glucose and saturated fat (FFA) levels may cause local factor changes affecting podocyte survival, an important vascular cell in kidney, which are not easily reversed. I made a very interesting finding on a potential target called SHP-1 that is elevated with high glucose concentrations in diabetic kidney of rodent animals. SHP-1 is a member of the protein tyrosine phosphatase family that downregulates the activity of important growth factors such as insulin, VEGF and nephrin, which are crucial for podocyte survival and function. Interestingly, insulin resistance caused by FFA is triggered by the activation of the protein kinase C (PKC)-alpha. Thus, unwanted abnormalities of renal podocyte function causing insulin resistance in T1D and T2D can be regulated by the activation of two independent pathways: SHP-1 and PKC-alpha. The aim of the present proposal will characterize and explore the role of SHP-1 and PKC-alpha activation producing biological abnormalities such as podocyte death and insulin resistance. To accomplish this aim, we will use several methods to specifically manipulate the protein expression level of SHP-1 and PKC-alpha in podocyte cell line and evaluate their impact on insulin and nephrin actions. Moreover, I will use genetically modified tissue specific mice of SHP-1 to characterize its cellular mechanisms implicated in diabetic nephropathy using a T1D and T2D mouse models. We believe that this proposal will help us better understand the mechanisms underlying renal cell dysfunction related to kidney failure in T1D and T2D.