Regulation of Transforming Growth Factor β in Diabetic Nephropathy: Implications for Treatment

Abstract

The recognition of the drivers of matrix accumulation as a therapeutic target for diabetic nephropathy is accepted by the Nephrology and pharmaceutical community. Interventions focused around Transforming Growth Factor-beta (TGF-β) will likely be an important area of clinical investigation in the near future. Understanding the various pathways involved in stimulating TGF-β in the diabetic kidney is of paramount importance in devising strategies to combat the development and progression of diabetic nephropathy. In this review we highlight the major pathways involved in stimulating TGF-β production by elevated glucose and discuss the therapeutic implications.

High glucose activates PKC-ζ and NADPH oxidase through autocrine TGF-β1 signaling in mesangial cells

“…Elevated expression of TGF-␤ 1 is a major stimulant for ECM accumulation by mesangial cells through regulation of genes encoding ECM, PAI-1, and other proteins through Smads and extracellular signal-regulated kinase (ERK) (13,17,18,19,29,36,44,57,68,69,71). In this study, we found for the first time that two initial effects of high ambient glucose, the generation of ROS by NADPH oxidase and activation of PKC-are dependent on signal transduction initiated by TGF-␤ 1 .…”

“…In diabetes, glomerular ECM protein expression and accumulation are regulated by peptide growth factors, such as platelet-derived growth factor, angiotensin II, and transforming growth factor (TGF)-␤ 1 (18,35,53,68,69). The most potent of these, TGF-␤ 1 , contributes to glomerular ECM accumulation by increasing the expression of ECM genes, such as collagen I and IV, and fibronectin and by decreasing ECM degradation through elevated expression of plasminogen activator inhibitor-1 (PAI-1) and other effects on mesangial cells (17,34,44).…”

“…The most potent of these, TGF-␤ 1 , contributes to glomerular ECM accumulation by increasing the expression of ECM genes, such as collagen I and IV, and fibronectin and by decreasing ECM degradation through elevated expression of plasminogen activator inhibitor-1 (PAI-1) and other effects on mesangial cells (17,34,44). TGF-␤ 1 expression and activation play a pathogenic role in mesangial expansion in diabetic nephropathy (68,69). In this regard, TGF-␤ 1 and its receptors are upregulated in both experimental and human diabetic nephropathy (21,56,57,68,69,65).…”

“…TGF-␤ 1 expression and activation play a pathogenic role in mesangial expansion in diabetic nephropathy (68,69). In this regard, TGF-␤ 1 and its receptors are upregulated in both experimental and human diabetic nephropathy (21,56,57,68,69,65). Enhanced expression of TGF-␤ 1 , TGF-␤ receptors, TGF-␤ 1 bioactivity, and responsiveness to exogenous TGF-␤ 1 have been noted to occur in response to high glucose in glomerular mesangial cells grown in tissue culture, an in vitro model for the effects of high glucose (19,21,29,41,68,69).…”

“…In this regard, TGF-␤ 1 and its receptors are upregulated in both experimental and human diabetic nephropathy (21,56,57,68,69,65). Enhanced expression of TGF-␤ 1 , TGF-␤ receptors, TGF-␤ 1 bioactivity, and responsiveness to exogenous TGF-␤ 1 have been noted to occur in response to high glucose in glomerular mesangial cells grown in tissue culture, an in vitro model for the effects of high glucose (19,21,29,41,68,69). Furthermore, inhibiting TGF-␤ 1 attenuates the high glucoseinduced changes in gene expression in mesangial cells that lead to the accumulation of ECM both in vitro and in animal models of diabetic nephropathy (29,45,70,71).…”