Abstract
Background. Podocyte injury plays an important role in the onset and progression of diabetic nephropathy (DN). Downregulation of α3β1-integrin expression in podocytes is thought to be associated with podocyte detachment from the glomerular basement membrane, although the mechanisms remain obscure. To determine the mechanism of podocyte detachment, we analyzed the expression levels of α3β1-integrin in podocytes in early and advanced stages of DN. Methods. Surgical specimens from DN patients were examined by in situ hybridization, and the expression levels of α3- and β1-integrin subunits in glomeruli of early (n = 6) and advanced (n = 8) stages were compared with those of normal glomeruli (n = 5). Heat-sensitive mouse podocytes (HSMP) were cultured with TGF-β1 to reproduce the microenvironment of glomeruli of DN, and the expression levels of integrin subunits and the properties of migration and attachment were examined. Results. Podocytes of early-stage DN showed upregulation of α3- and β1-integrin expression while those of advanced stage showed downregulation. Real-time PCR indicated a tendency for upregulation of α3- and β1-integrin in HSMP cultured with TGF-β1. TGF-β1-stimulated HSMP also showed enhanced in vitro migration and attachment on collagen substrate. Conclusions. The results suggested that podocyte detachment during early stage of DN is mediated through upregulation of α3β1-integrin.
Highlights
Diabetic nephropathy (DN) is one of the major indications for hemodialysis treatment in patients with diabetes mellitus (DM)
Since no proliferation of mature podocytes is noted in the majority of nephropathies, including diabetic nephropathy (DN) [30], integrin mRNA overexpression in podocytes, including higher percentage of integrin-positive cells in DN1 glomeruli, can be detected by in situ hybridization
Several studies involving DN patients and animal models reported a decrease or no change in α3β1-integrin expression in podocytes, almost all of them assessed the expression of integrin in podocytes of proceeded stage of DN in patients and animals [20,21,22,23]
Summary
Diabetic nephropathy (DN) is one of the major indications for hemodialysis treatment in patients with diabetes mellitus (DM). The results of studies involving DN patients, animal models of DN, and in vitro culture of podocytes under high glucose conditions have so far demonstrated underexpression of α3-integrin subunit in podocytes and suggested that the main cause of podocyte detachment was a decrease in the number of α3β1-integrins on the surface of podocytes [20,21,22,23]. Downregulation of α3β1-integrin expression in podocytes is thought to be associated with podocyte detachment from the glomerular basement membrane, the mechanisms remain obscure. Heat-sensitive mouse podocytes (HSMP) were cultured with TGF-β1 to reproduce the microenvironment of glomeruli of DN, and the expression levels of integrin subunits and the properties of migration and attachment were examined. The results suggested that podocyte detachment during early stage of DN is mediated through upregulation of α3β1-integrin
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