Regulation of Podocyte apoptosis in Diabetic Kidney Disease - Role of SHIP2, PDK1 and CDK2
Year: 2016
Type: dissertation
Abstract: Background: Diabetic nephropathy (DN) is a renal complication of diabetes and a common cause of end-stage renal disease (ESRD). DN presents in its earliest stage with low levels of albumin in the urine (microalbuminuria) and develops into overt albuminuria as the disease progresses. Podocyte loss due to detachment or apoptosis has a central role in the pathogenesis of DN, but the mechanisms are not fully understood. The studies in this thesis aimed to increase the knowledge of the pathophysiological mechanisms and molecular pathways leading to podocyte apoptosis in DN by studying three molecules that are expressed in podocytes, SH2-domain-containing inositol polyphosphate 5-phosphate 2 (SHIP2), 3-phosphoinositide-dependent kinase 1 (PDK1) and cyclindependent kinase 2 (CDK2). Results: Lipid phosphatase SHIP2 was identified as an interaction partner of CD2AP, a protein known to be involved in the regulation of apoptosis in podocytes. We found that overexpression of SHIP2 in cultured podocytes reduced the phosphorylation of the major cell survival kinase Akt in response to insulin and increased apoptosis. We also observed that the expression of SHIP2 was upregulated in glomeruli of insulin resistant obese Zucker rats prior to the onset of proteinuria, suggesting a role for SHIP2 in the development of podocyte injury. In contrast, we found that the expression of PDK1 and CDK2 was downregulated in obese Zucker rats before they had developed proteinuria. We also observed that treatment of human podocytes with sera from normoalbuminuric type 1 diabetic (T1D) patients with high lipopolysaccharide (LPS) activity downregulated the expression of PDK1 and CDK2. LPS treatment of mice in vivo also reduced PDK1 and CDK2 expression. LPS-induced downregulation of PDK1 and CDK2 was prevented both in vitro and in vivo by inhibition of the toll-like receptor (TLR) pathway using immunomodulatory agent GIT27. Knockdown of either PDK1, or CDK2 inhibited antiapoptotic Akt pathway, stimulated the proapoptotic p38 MAPK pathway and increased podocyte apoptosis. Conclusions: Given the central role of the PI3K-dependent Akt signaling pathway in regulating cell survival, our findings suggest that SHIP2, PDK1 and CDK2 regulate apoptosis in podocytes by modulating the activity of the PI3K-dependent Akt signaling pathway.
Source: Työväentutkimus Vuosikirja
Author: Pauliina Saurus
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2280011078