TGF-β1-induced PINCH-1-ILK-α-parvin complex formation regulates mesangial cell proliferation and hypertrophy

Abstract

TGF-β1-induced glomerular mesangial cell (GMC) injury is a prominent characteristic of renal pathology in several kidney diseases, and a ternary protein complex consisting of PINCH-1, integrin-linked kinase (ILK) and α-parvin plays a pivotal role in the regulation of cell behavior such as cell proliferation and hypertrophy. We report here that PINCH-1-ILK-α-parvin (PIP) complex regulates the TGF-β1-induced cell proliferation and hypertrophy in cultured rat GMCs. When GMCs were treated with TGF-β1 for 1, 2 and 3 days, the PIP complex formation was up-regulated after 1 day, but it was down-regulated on day 2. Cell numbers were significantly elevated on day 2, but dramatically decreased on day 3. In contrast, a significant increase in cellular protein contents was observed 3 days after TGF-β1-treatment. TGF-β1 induced early increase of caspase-3 activity. In GMCs incubated with TGF-β1 for 2 days, cytosolic expression of p27 Kip1 was dramatically reduced, but its nuclear expression was remarkably elevated. A significantly decreased expression of phospho-Akt (Ser 473) was observed in the cells treated with TGF-β1 for 1 day. TGF-β1 induced early increase of phospho-p27 Kip1 (Thr 157) expression with subsequent decrease, and similar responses to TGF-β1 were observed in the p38 phosphorylation (Thr 180/Thr 182). Taken together, TGF-β1 differently regulates the PIP complex formation of GMCs in an incubation period-dependant fashion. The TGF-β1-induced up-and down-regulation of the PIP complex formation likely contributes to the pleiotropic effects of TGF-β1 on mesangial cell proliferation and hypertrophy through cellular localization of p27Kip1 and alteration of Akt and p38 phosphorylation. TGF-β1-induced alteration of the PIP complex formation may be importantly implicated in the development and progression of glomerular failure shown in several kidney diseases.

High glucose enhances TGF-β1 expression in rat bone marrow stem cells via ERK1/2-mediated inhibition of STAT3 signaling

“…Lee., 2000), and hypoxia (Lee et al, 2009). It is well documented that HG enhances TGF-β1 expression in mesangial cells, vascular endothelial cells, and retinal pigment epithelial cells (Wu et al, 2009;Chen et al, 2007;Kim et al, 2007aKim et al, , 2007bHayashida and Schnaper, 2004;Isono et al, 2000). The increased TGF-β1 activity is considered to contribute to the development of endothelial dysfunction and micro-and macrovascular complications in diabetes mellitus diabetic nephropathy (Hayashida and Schnaper, 2004;Belmadani et al, 2008).…”

“…Protein kinase C and Akt signaling as well as the transcription factor AP-1 are involved in glucose-induced TGF-β1 upregulation in mesangial cells and human MSCs (Wu et al, 2009;Ryu et al, 2010). ERK1/2 and P38 MAPK pathways also play an important role in HG-induced increase in TGF-β1 expression in mesangial cells, vascular endothelial cells, and retinal pigment epithelial cells (Chen et al, 2007;Kim et al, 2007aKim et al, , 2007bHayashida and Schnaper, 2004;Isono et al, 2000;Fujita et al, 2004). In the present study, we demonstrated that HG upregulated TGF-β1 expression in rat MAPCs through ERK1/2-mediated inhibition of STAT3 signaling.…”

“…TGF-β1 is expressed in many types of cells including endothelial cells, smooth muscle cells, mesangial cell and MSCs (Vinals and Pouyssegur, 2001;Redondo et al, 2007;Kim et al, 2007aKim et al, , 2007bWorster et al, 2000). The regulation of TGF-β1 expression and function is very complex and tightly controlled, and involves a variety of factors including angiotensin II (Ang II), aldosterone (Han et al, 2009), basic fibroblast growth factor (Dhandapani et al, 2007), tumor necrosis factor alpha (Sullivan et al, 2008), aryl hydrocarbon receptor (Gramatzki et al, 2009), B-type natriuretic peptide (He et al, 2010), tetrachlorodibenzo-p-dioxin (Jin et al, 2008), hepatitis B virus X protein (Guo et al, 2009), reactive oxygen species (Ha and Fig.…”

Benazepril affects integrin-linked kinase and smooth muscle α-actin expression in diabetic rat glomerulus and cultured mesangial cells

“…Transforming growth factor-β 1 (TGF-β 1 ) can induce the accumulation of extracellular matrix (ECM) components, including collagens, fibronectin (FN) and laminin in the glomeruli and the interstitium of the kidney. TGF-β 1 expression regulates PINCH-1-integrin-linked kinase (ILK)-alpha-parvin complex formation and contributes to glomerular mesangial cell (GMC) proliferation and hypertrophy [4]. ILK, a cytoplasmic-binding serine/threonine protein kinase, is physically connected to the actin cytoskeleton and actin-binding protein CH-ILKBP, which is an important step in the development and progression of glomerular failure observed in several kidney diseases [5].…”

The function of p27KIP1during tumor development

“…In addition, the null mice also display female sterility due to defective ovarian and uterine function (Fero et al, 1996;Chien et al, 2007;Kim et al, 2007). The tumor suppressive activity of p27 KIP1 using null mice was first demonstrated by development of adenomas in the intermediate lobe of the pituitary gland, and by their inclination to develop tumors more easily when challenged with chemical carcinogens or irradiation (Nakayama et al, 1996).…”