Transforming Growth Factor-β1 Stimulates Vascular Endothelial Growth Factor 164 via Mitogen-activated Protein Kinase Kinase 3-p38α and p38δ Mitogen-activated Protein Kinase-dependent Pathway in Murine Mesangial Cells

Wang, Lin; Kwak, Joon Hyeok; Kim, Sung Il; He, Yanjuan; Choi, Mary E.

doi:10.1074/jbc.m403758200

Cited by 57 publications

(50 citation statements)

References 50 publications

(46 reference statements)

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“…Here, we examined the role of the MKK3 signaling pathway in mediating the CO effects in UUO. MKK3 is one of the immediate upstream MAPK kinase required for activation of p38 MAPK (49,50). In our present study, the anti-fibrotic effects of CO treatment were abrogated in mice carrying a null mutation of MAPK kinase 3 (Mkk3 Ϫ/Ϫ ).…”

Section: Discussionsupporting

confidence: 47%

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Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction

Wang¹,

Lee²,

Kwak³

et al. 2008

American Journal of Physiology-Renal Physiology

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Tubulointerstitial fibrosis is a hallmark of chronic progressive kidney disease leading to end-stage renal failure. An endogenous product of heme oxygenase activity, carbon monoxide (CO), has been shown to exert cytoprotection against tissue injury. Here, we explored the effects of exogenous administration of low-dose CO in an in vivo model of renal fibrosis induced by unilateral ureteral obstruction (UUO) and examined whether CO can protect against kidney injury. UUO in mice leads to increased extracellular matrix (ECM) deposition and tubulointerstitial fibrosis within 4 to 7 days. Kidneys of mice exposed to low-dose CO, however, had markedly reduced ECM deposition after UUO. Moreover, low-dose CO treatment inhibited the induction of α-smooth muscle actin (α-SMA) and major ECM proteins, type 1 collagen and fibronectin, in kidneys after UUO. In contrast, these anti-fibrotic effects of CO treatment were abrogated in mice carrying null mutation of Mkk3, suggesting involvement of the MKK3 signaling pathway in mediating the CO effects. Additionally, in vitro CO exposure markedly inhibited TGF-β1-induced expression of α-SMA, collagen, and fibronectin in renal proximal tubular epithelial cells. Our findings suggest that low-dose CO exerts protective effects, via the MKK3 pathway, to inhibit development of renal fibrosis in obstructive nephropathy.

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Section: Discussionsupporting

confidence: 47%

“…The blots were exposed to Kodak X-AR film. The human pro-␣1(I) collagen cDNA and fibronectin cDNA were obtained from ATCC and previously described (49). To control for relative equivalence of RNA loading, the same blots were hybridized with 32 P-labeled oligonucleotide probes corresponding to the 18S rRNA as previously described (49).…”

Section: Methodsmentioning

confidence: 99%

Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction

Wang¹,

Lee²,

Kwak³

et al. 2008

American Journal of Physiology-Renal Physiology

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“…tor-␤ selectively activates MKK3-p38␣/p38␦ but MKK6 and p38␤ in murine mesangial cells (43,44). ␥-Irradiation preferentially activates the MKK6-p38␥ pathway in human osteosarcoma cells (45).…”

Section: P38 Mapk Upa and Endothelial Cell Migrationmentioning

confidence: 99%

p38 Mitogen-activated Protein Kinase Regulation of Endothelial Cell Migration Depends on Urokinase Plasminogen Activator Expression

Bian

Mahanivong

et al. 2004

Journal of Biological Chemistry

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The migration of endothelial cells in response to various stimulating factors plays an essential role in angiogenesis. The p38 MAPK pathway has been implicated to play an important role in endothelial cell migration because inhibiting p38 MAPK activity down-regulates vascular endothelial growth factor (VEGF)-stimulated migration. Currently, the signaling components in the p38 MAPK activation pathway and especially the mechanisms responsible for p38 MAPK-regulated endothelial cell migration are not well understood. In the present study, we found that p38 MAPK activity is required for endothelial cell migration stimulated by both VEGF and nongrowth factor stimulants, sphingosine 1-phosphate and soluble vascular cell adhesion molecule. By using dominant negative forms of signaling components in the p38 MAPK pathway, we identified that a regulatory pathway consisting of MKK3-p38␣/␥-MAPK-activated protein kinase 2 participated in VEGF-stimulated migration. In further studies, we showed that a minimum of a 10-h treatment with SB203580 (specific p38 MAPK inhibitor) was needed to block VEGF-stimulated migration, suggesting an indirect role of p38 MAPK in this cellular event. Most interestingly, the occurrence of SB203580-induced migratory inhibition coincided with a reduction of urokinase plasminogen activator (uPA) expression. Furthermore, agents disrupting uPA and uPA receptor interaction abrogated VEGF-stimulated cell migration. These results suggest a possible association between cell migration and uPA expression. Indeed, VEGF-stimulated migration was not compromised by SB203580 in endothelial cells expressing the uPA transgene; however, VEGF-stimulated migration was inhibited by agents disrupting uPA-uPA receptor interaction. These results thus suggest that the p38 MAPK pathway participates in endothelial cell migration by regulating uPA expression.

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“…Genetically modified Mkk3 −/− and Mkk6 −/− mice are viable and fertile, and provide an opportunity to study the role of p38 signalling in models of disease. Of these two kinases, MKK3 appears to be the most attractive target for studies of genetic deletion, because MKK3-p38 signalling has been shown to be nonredundant in some pathological processes [30,31]. Furthermore, mouse studies have shown that Mkk3 deficiency is protective in models of passive arthritis and streptozotocin-induced pancreatic inflammation [32,33].…”

Section: Introductionmentioning

confidence: 99%

Role of MKK3–p38 MAPK signalling in the development of type 2 diabetes and renal injury in obese db/db mice

et al. 2008

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Aims/hypothesis Obesity and diabetes are associated with increased intracellular p38 mitogen-activated protein kinase (MAPK) signalling, which may promote tissue inflammation and injury. Activation of p38 MAPK can be induced by either of the immediate upstream kinases, MAP kinase kinase (MKK)3 or MKK6, and recent evidence suggests that MKK3 has non-redundant roles in the pathology attributed to p38 MAPK activation. Therefore, this study examined whether MKK3 signalling influences the development of obesity, type 2 diabetes and diabetic nephropathy. Methods Wild-type and Mkk3 (also known as Map2k3) gene-deficient db/db mice were assessed for the development of obesity, type 2 diabetes and renal injury from 8 to 32 weeks of age. Results Mkk3+/+ db/db and Mkk3 −/− db/db mice developed comparable obesity and were similar in terms of incidence and severity of type 2 diabetes. At 32 weeks, diabetic Mkk3 +/+ db/db mice had increased kidney levels of phospho-p38 and MKK3 protein. In comparison, kidney levels of phospho-p38 in diabetic Mkk3 −/− db/db mice remained normal, despite a fourfold compensatory increase in MKK6 protein levels. The reduced levels of p38 MAPK signalling in the diabetic kidneys of Mkk3 −/− db/ db mice was associated with protection against the following: declining renal function, increasing albuminuria, renal hypertrophy, podocyte loss, mesangial cell activation and glomerular fibrosis. Diabetic Mkk3 −/− db/db mice were also significantly protected from tubular injury and interstitial fibrosis, which was associated with reduced Ccl2 mRNA expression and interstitial macrophage accumulation. Conclusions/interpretation MKK3-p38 MAPK signalling is not required for the development of obesity or type 2 diabetes, but plays a distinct pathogenic role in the progression of diabetic nephropathy in db/db mice.

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Transforming Growth Factor-β1 Stimulates Vascular Endothelial Growth Factor 164 via Mitogen-activated Protein Kinase Kinase 3-p38α and p38δ Mitogen-activated Protein Kinase-dependent Pathway in Murine Mesangial Cells

Cited by 57 publications

References 50 publications

Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction

Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction

p38 Mitogen-activated Protein Kinase Regulation of Endothelial Cell Migration Depends on Urokinase Plasminogen Activator Expression

Role of MKK3–p38 MAPK signalling in the development of type 2 diabetes and renal injury in obese db/db mice

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