Experimental and genetic studies on podocyte molecules CD2AP and SHIP2 in diabetic nephropathy
Year: 2013
Type: dissertation
Abstract: Diabetic nephropathy is the renal complication of diabetes. It is associated with high mortality, especially for cardiovascular disease. Many of the risk factors and metabolic features, such as insulin resistant and inflammatory state, are shared between the renal and cardiovascular complications. Diabetic nephropathy is known to cluster in families, but its genetic background has not been revealed. Podocyte injury has a central role in the pathogenesis of diabetic nephropathy, but the mechanisms are far from completely understood. The studies in this thesis aimed to increase the knowledge of the pathophysiological processes of diabetic nephropathy by studying two molecules expressed in podocytes, CD2AP and SHIP2, and by characterising the development of the renal injury in a mouse model with early-onset diabetes. Lipid phosphatase SHIP2 was identified as a new interaction partner of CD2AP, an adaptor protein essential for podocyte function. SHIP2 was shown to be expressed in the glomerular podocytes, and to be translocated to the plasma membrane in response to insulin. The interaction of CD2AP and SHIP2 was not dependent on insulin stimulation, in contrast, CD2AP was found to bind only to the non-tyrosine-phosphorylated form of SHIP2. Overexpression of SHIP2 in cultured podocytes was found to reduce the activation of protein kinase Akt in response to insulin, and to promote apoptosis. Elevated expression of SHIP2 was detected in the glomeruli of diabetic mice and rats. A candidate gene approach was used to investigate if polymorphisms in CD2AP or INPPL1 (encoding for SHIP2 protein) genes are associated with diabetic nephropathy. The study subjects were from the Finnish Diabetic Nephropathy Study, and they all had type 1 diabetes. CD2AP and INPPL1 genes were not associated with diabetic nephropathy per se, but INPPL1 was associated with the metabolic syndrome in male patients with diabetes, and CD2AP with end stage renal disease in patients with diabetes. The associations between polymorphisms in the CD2AP gene and end stage renal disease were confirmed in meta-analysis of the original and additional European cohorts. The transgenic E1-DN mice are diabetic due to impaired postnatal growth of β-cell mass. The renal injury is secondary to persistent hyperglycaemia. The homozygous E1-DN mice were found to develop albuminuria, and histological and structural changes including mesangial expansion, thickening of the glomerular basement membrane and podocyte foot process widening. Reduced expression of nephrin, increased glomerular apoptosis and tubular proliferation were identified as potential mechanisms of renal injury. The upregulation of SHIP2 demonstrates a possible mechanism for insulin resistance in podocytes, and may be involved in increased podocyte apoptosis in diabetes. The results of the genetic analyses suggest that variants in INPPL1 gene may contribute to susceptibility to the metabolic syndrome, and variants in the CD2AP gene to susceptibility to end stage renal disease, in patients with type 1 diabetes. Diabetic E1-DN mice develop substantial albuminuria and glomerular injury resembling human diabetic nephropathy and can serve as a new model to study the mechanisms of diabetic nephropathy.
Source: Työväentutkimus Vuosikirja
Author: Hyvönen, Mervi
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Vaasan Keskussairaala, Tays
OpenAlex ID: W1957787658