MAPK signaling and the kidney

Tian, Wei; Zhang, Zheng; Cohen, David

doi:10.1152/ajprenal.2000.279.4.f593

Cited by 145 publications

(127 citation statements)

References 174 publications

(155 reference statements)

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“…P38 MAPK (p38) is a member of the MAPK family and is in close association with a variety of renal diseases 20, 21, 22. We found hyper‐activity of p38 was driven by ox‐LDL, compared with the controls ( P < 0.05; Fig.…”

Section: Resultsmentioning

confidence: 76%

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F‐actin re‐organization via activating p38 in response to ox‐LDL

Fan

Zhen

et al. 2016

J Cellular Molecular Medi

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Focal adhesion kinase (FAK) is a non‐receptor protein tyrosine kinase that regulates cell adhesion, proliferation and differentiation. In the present study, a rat model of high fat diet‐induced hypercholesterolaemia was established to investigate the involvement of FAK in lipid disorder‐related kidney diseases. We showed focal fusion of podocyte foot process that occurred at as early as 4 weeks in rats consuming high fat diet, preceding the onset of proteinuria when aberrant phosphorylation of FAK was found. These abnormalities were ameliorated by dietary intervention of TAE226, a reported inhibitor of FAK. FAK is also an adaptor protein initiating cascades of intracellular signals including c‐Src, Rho GTPase and mitogen‐activated protein kinase (MAPK). P38 MAPK belongs to the latter and is centrally involved in kidney diseases. Our cell culture data revealed oxidized low‐density lipoprotein (ox‐LDL) triggered hyper‐phosphorylation of FAK and p38, ectopic expression of cellular markers (manifested as decreased WT1, podocin and NEPH1, and increased vimentin and mmp9), and re‐arrangement of F‐actin filaments with enhanced cell motility; these mutations were significantly rectified by FAK shRNA. Notably, pre‐treatment of p38 inhibitor did not alter FAK activation, albeit its deletion of p38 hyper‐activity and attenuation of cellular abnormalities, demonstrating that p38 acted as a downstream effector of FAK signalling and ox‐LDL damaged podocytes in a FAK/p38‐dependent manner. This was further identified by animal data that p38 activation was also abrogated by TAE226 treatment in hypercholesterolaemic rats, suggesting that FAK/p38 axis might also be involved in in vivo events. These findings provided a potential early mechanism of hypercholesterolaemia‐related podocyte damage and proteinuria.

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Section: Resultsmentioning

confidence: 76%

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F‐actin re‐organization via activating p38 in response to ox‐LDL

Fan

Zhen

et al. 2016

J Cellular Molecular Medi

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“…However, the number of kidney p-p38+ cells in diabetic db/db mice did not correlate with blood cholesterol or triglycerides, and obese db/db mice with normal blood glucose and HbA 1 c levels had similar numbers of kidney p-p38+ cells to normal animals, which suggests that obesity is unlikely to play an important role in promoting p38 phosphorylation in the kidney in Type 2 diabetic nephropathy. Other pathological features of diabetic nephropathy, such as increased oxidative and osmotic stress, hypertension, cytokine release and renin/angiotensin responses, are also thought to potentially contribute to the induction of kidney p38 signalling [27]. These factors were not evaluated here.…”

Section: Discussionmentioning

confidence: 99%

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy

et al. 2004

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Aims/hypothesis. Inflammation and fibrosis are pathological mechanisms that are partially regulated by cell signalling through the p38 mitogen-activated protein kinase (MAPK) pathway. Elements of the diabetic milieu such as high glucose and advanced glycation endproducts induce activation of this pathway in renal cells. Therefore, we examined whether p38 MAPK signalling is associated with the development of human and experimental diabetic nephropathy. Methods. Immunostaining identified phosphorylated (active) p38 MAPK in human biopsies with no abnormality (n=6) and with Type 2 diabetic nephropathy (n=12). Changes in kidney levels of phosphorylated p38 were assessed by immunostaining and western blotting in mice with streptozotocin-induced Type 1 diabetes that had been killed after 0.5, 2, 3, 4 and 8 months, and in Type 2 diabetic db/db mice at 2, 4, 6 and 8 months of age. Results. Phosphorylated p38 was detected in some intrinsic cells in normal human kidney, including podocytes, cortical tubules and occasional interstitial cells. Greater numbers of these phosphorylated p38+ cells were observed in diabetic patients, and phosphorylated p38 was identified in accumulating interstitial macrophages and myofibroblasts. A similar pattern of p38 activation was observed in both mouse models of diabetes. In mice, kidney levels of phosphorylated p38 increased (2-6 fold) following the onset of Type 1 and Type 2 diabetes. In both mouse models, interstitial phosphorylated p38+ cells were associated with hyperglycaemia, increased HbA 1 c levels and albuminuria. Further assessment of streptozotocin-induced diabetic nephropathy showed that interstitial phosphorylated p38+ cells correlated with interstitial fibrosis (myofibroblasts, collagen). Conclusions/interpretation. Increased p38 MAPK signalling is a feature of human and experimental diabetic nephropathy. Time course studies in mouse models suggest that phosphorylation of p38 plays a pathological role, particularly in the development of interstitial fibrosis.

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“…However, it was reported recently that a fourth subfamily (ERK5 pathway) also has a critical function in the mediation of apoptosis [18] . Therefore, we examined the total and phosphorylated expression levels of the MAPK family members ERK1/2, JNK, p38, and ERK5 in mig-2-mediated cisplatin-induced apoptosis.…”

Section: Wwwchinapharcom Ou Yw Et Almentioning

confidence: 99%

Mig-2 attenuates cisplatin-induced apoptosis of human glioma cells in vitro through AKT/JNK and AKT/p38 signaling pathways

Ou¹,

Zhao

et al. 2014

Acta Pharmacol Sin

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Aim: Mig-2 (also known as Kindlin-2 and FERMT2) is an important regulator of integrin activation and cell-extracellular matrix adhesion, and involved in carcinogenesis and tumor progression. The aim of this study was to investigate the role of mig-2 in cisplatin-induced apoptosis of human glioma cells in vitro. Methods: The expression of mig-2 was modulated in human glioma H4, HS 683 and U-87 MG cells by transfection with a plasmid carrying mig-2 or mig-2 siRNA. Cisplatin-induced apoptosis was detected using Annexin V/PI staining and flow cytometry, as well as MTS analyses. The expression of apoptosis-related or signaling proteins was examined using Western blotting analysis. H4 cells were transfected with plasmids carrying mig-2 mutants to determine the functional domain of mig-2. Results: In the 3 glioma cell lines tested, overexpression of mig-2 significantly attenuated cisplatin-induced apoptosis, whereas knockdown of mig-2 potentiated the apoptosis. The mechanisms of action of mig-2 were further addressed in H4 cells: overexpression of mig-2 markedly reduced cleaved caspase-9, caspase-8, caspase-3 and PARP, as well as p-JNK and p-p38, and increased p-AKT in cisplatin-treated H4 cells, whereas mig-2 siRNA reversely changed these apoptosis-related and signaling proteins. Furthermore, pretreatment with JNK inhibitor SP600125 and p38 inhibitor SB203580, or with AKT inhibitor LY294002 abolished the effects of mig-2 on cisplaxtin-induced apoptosis. In H4 cells, GFP-mig-2 F3 plasmid that contained only the F3 subdomain showed the same efficiency in attenuating cisplatin-induced apoptosis, as the mig-2 wild-type vector did, whereas GFP-mig-2 (1-541) plasmid that lacked the F3 subdomain was inactive. Conclusion: Mig-2 significantly attenuates the antitumor action of cisplatin against human glioma cells in vitro through AKT/JNK and AKT/p38 signaling pathways. The F3 subdomain of mig-2 is necessary and sufficient for this effect.

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MAPK signaling and the kidney

Cited by 145 publications

References 174 publications

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F‐actin re‐organization via activating p38 in response to ox‐LDL

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F‐actin re‐organization via activating p38 in response to ox‐LDL

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy

Mig-2 attenuates cisplatin-induced apoptosis of human glioma cells in vitro through AKT/JNK and AKT/p38 signaling pathways

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