Differential Contribution of Three Mitogen-Activated Protein Kinases to PDGF-BB-Induced Mesangial Cell Proliferation and Gene Expression

Abstract

Abstract. This study examined the role of mitogen-activated protein (MAP) kinase in PDGF-BB-induced proliferation and gene expression of human mesangial cells (MC). PDGF-BB stimulation of MC increased mRNA for transforming growth factor-␤1 (TGF-␤1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) and increased the cell numbers. To inhibit activation of extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38, MC were infected with recombinant adenovirus containing dominant-negative mutants of ERK, JNK, and p38 (Ad-DN-ERK, Ad-DN-JNK, Ad-DN-p38, respectively), respectively. Infection of MC with Ad-DN-ERK or Ad-DN-JNK inhibited PDGF-BBinduced increase in [ 3 H]thymidine incorporation and cell numbers, whereas Ad-DN-p38 did not. Ad-DN-ERK inhibited MCP-1 and PAI-1 mRNA expression in MC, but not TGF-␤1. Ad-DN-JNK and Ad-DN-p38 inhibited TGF-␤1 and MCP-1 mRNA expression, but not PAI-1. The inhibition of activator protein-1 (AP-1) in MC, by adenovirus containing dominant-negative mutant of c-Jun (Ad-DN-c-Jun), inhibited PDGF-BB-induced cell proliferation and TGF-␤1, MCP-1, and PAI-1 expressions. Furthermore, Ad-DN-JNK or Ad-DN-p38, but not Ad-DN-ERK, attenuated PDGF-BB-induced AP-1 activation in MC, indicating the involvement of JNK and p38 in AP-1 activation. Our results indicated that ERK and JNK, but not p38, participated in PDGF-BB-induced MC proliferation. PDGF-BB-induced expression of TGF-␤1 was mediated by JNK and p38, MCP-1 expression was through ERK, JNK, and p38, whereas PAI-1 expression was due to only ERK. AP-1 activation, which was partially due to JNK and p38 activations, was involved in MC proliferation and these three gene expressions. Thus, three MAP kinases seem to contribute to progression of glomerular disease via different molecular mechanisms.

Hydrogen Sulfide Alleviates Diabetic Nephropathy in a Streptozotocin-induced Diabetic Rat Model

“…MAPK signaling pathways, which promote cell cycle progression by regulating the expression of cyclin-dependent kinases, are critically involved in the proliferation of mesangial cells (17). Our findings in this study indicated that ERK1/2, JNK, and p38 MAPK signaling was activated in mesangial cells exposed to high glucose, which might be an important molecular mechanism responsible for mesangial cell proliferation.…”

n-3 Fatty acids block TNF-α-stimulated MCP-1 expression in rat mesangial cells

“…In renal tubular epithelial cells, the MEK inhibitor U0126 prevents induction of MCP-1 in response to a variety of stimuli, including TNF-␣, albumin, and osmotic stress (27,34,71). In MCs, a dominant-negative ERK construct inhibits PDGF-stimulated MCP-1 production (31). We previously demonstrated that n-3 fatty acids decrease EGF-stimulated ERK activation in cultured MCs (78).…”

c-Jun NH2-Terminal Kinase Is Crucially Involved in Renal Tubulo-Interstitial Inflammation

“…Overexpression of c-Jun induces MCP-1 gene expression (Wang et al, 1999). JNK is also involved in MCP-1 expression in other cell types, including renal mesangial cells (Kawano et al, 2003) and vascular smooth muscle cells (Chen et al, 2004), but previous data on the involvement of JNK in MCP-1 expression in cultured human and mouse tubular epithelial cells have been conflicting (Tsuboi et al, 2002;Sengul et al, 2003).…”