+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Transforming growth factor-beta1 stimulates vascular endothelial growth factor 164 via mitogen-activated protein kinase kinase 3-p38alpha and p38delta mitogen-activated protein kinase-dependent pathway in murine mesangial cells



Transforming growth factor-beta1 stimulates vascular endothelial growth factor 164 via mitogen-activated protein kinase kinase 3-p38alpha and p38delta mitogen-activated protein kinase-dependent pathway in murine mesangial cells



Journal of Biological Chemistry 279(32): 33213-9



Transforming growth factor-beta1 (TGF-beta1) is a potent inducer of extracellular matrix synthesis leading to progressive glomerular fibrosis. The intracellular signaling mechanisms involved in this process remain incompletely understood. The p38 mitogen-activated protein kinase ( MAPK) is a major stress signal transducing pathway that is rapidly activated by TGF-beta1 in mesangial cells. We have previously demonstrated MKK3 as the immediate upstream MAPK kinase required for selective activation of p38 MAPK isoforms, p38alpha and p38delta, and stimulation of pro-alpha1( I) collagen by TGF-beta1 in murine mesangial cells. In this study, we further sought to determine MAPK kinase 3 ( MKK3)-dependent TGF-beta1 responses by gene expression profiling analysis utilizing mesangial cells isolated from Mkk3(-/-) mice compared with Mkk3(+/+) controls. Interestingly, vascular endothelial growth factor ( VEGF) was identified as a TGF-beta1-induced gene affected by deletion of Mkk3. VEGF is a well known endothelial mitogen, whose actions in nonendothelial cell types are still not well understood. We confirmed that TGF-beta1 increased VEGF mRNA and protein synthesis of VEGF164 and VEGF188 isoforms in wild-type mesangial cells. However, in the Mkk3(-/-) mesangial cells, both TGF-beta1-induced VEGF mRNA and VEGF164 protein expression were inhibited, whereas TGF-beta1-induced VEGF188 protein expression was unaffected. Furthermore, transfection of dominant negative mutants of p38alpha and p38delta resulted in marked inhibition of TGF-beta1-induced VEGF164 expression but not VEGF188, and treatment with recombinant mouse VEGF164 increased collagen and fibronectin mRNA expression in mesangial cells. Taken together, our findings suggest a critical role for the MKK3-p38alpha and p38delta MAPK pathway in mediating VEGF164 isoform-specific stimulation by TGF-beta1 in mesangial cells. Further, VEGF164 stimulates collagen and fibronectin expression in mesangial cells and thus in turn enhances TGF-beta1-induced extracellular matrix and may play an important role in progressive glomerular fibrosis.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 012705079

Download citation: RISBibTeXText

PMID: 15143069

DOI: 10.1074/jbc.m403758200


Related references

Transforming Growth Factor-b1 Stimulates Vascular Endothelial Growth Factor 164 via Mitogen-activated Protein Kinase Kinase 3-p38a and p38 Mitogen-activated Protein Kinase-dependent Pathway in Murine Mesangial Cells. Journal of Biological Chemistry 279(32): 213-19, 2004

Mitogen-activated protein kinase kinase 3 - p38 MAPK pathway mediates TGF-beta1 induced-expression of vascular endothelial growth factor in mouse mesangial cell. Journal of the American Society of Nephrology 14(Abstracts Issue): 406A, 2003

Basic fibroblast growth factor stimulates vascular endothelial growth factor release in osteoblasts: divergent regulation by p42/p44 mitogen-activated protein kinase and p38 mitogen-activated protein kinase. Journal of Bone and Mineral Research 15(12): 2371-2379, 2000

Selective activation of p38 MAPK isoforms p38alpha and p38delta by TGF-beta1 is mediated via mitogen-activated protein kinase kinase 3 in mouse mesangial cells. Journal of the American Society of Nephrology 13(Program and Abstracts Issue): 15A-16A, 2002

Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for activation of p38alpha and p38delta MAPK isoforms by TGF-beta 1 in murine mesangial cells. Journal of Biological Chemistry 277(49): 47257-47262, 2002

Nerve growth factor induces vascular endothelial growth factor expression in granulosa cells via a trkA receptor/mitogen-activated protein kinase-extracellularly regulated kinase 2-dependent pathway. Journal of Clinical Endocrinology and Metabolism 94(8): 3065-3071, 2009

Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3. Molecular Biology of the Cell 14(2): 529-544, 2003

Antioxidants inhibit transforming growth factor-beta1 autoinduction in human mesangial cells The role of the p38 mitogen activated protein kinase pathway. Journal of the American Society of Nephrology 12(Program and Abstract Issue): 850A, 2001

Role of platelet-derived growth factor-B, vascular endothelial growth factor, insulin-like growth factor-II, mitogen-activated protein kinase and transforming growth factor-beta1 in expansion-induced lung growth in fetal sheep. Reproduction Fertility and Development 18(6): 655-665, 2006

Transforming growth factor-beta1 induces apoptosis in vascular endothelial cells by activation of mitogen-activated protein kinase. Surgery 132(2): 173-179, 2002

Ras- and mitogen-activated protein kinase kinase-dependent and -independent pathways in p21Cip1/Waf1 induction by fibroblast growth factor-2, platelet-derived growth factor, and transforming growth factor-beta1. Cell Growth and Differentiation 10(9): 621-628, 1999

Transforming growth factor beta stimulates interleukin-6 production by human mesangial cells; involvement of p38 mitogen activated protein kinase pathway. Journal of the American Society of Nephrology 10(PROGRAM AND ABSTR ISSUE): 522A, 1999

Involvement of protein kinase C-dependent mitogen-activated protein kinase p44/42 signaling pathway for cross-talk between estradiol and transforming growth factor-beta3 in increasing basic fibroblast growth factor in folliculostellate cells. Endocrinology 145(2): 706-715, 2004

Mechanical stretch-induced fibronectin and transforming growth factor-beta1 production in human mesangial cells is p38 mitogen-activated protein kinase-dependent. Diabetes 49(4): 655-661, 2000

AICAR induces cyclooxygenase-2 expression through AMP-activated protein kinase-transforming growth factor-beta-activated kinase 1-p38 mitogen-activated protein kinase signaling pathway. Biochemical Pharmacology 80(8): 1210-1220, 2010