Roles of MEK/ERK Pathway in Vascular and Renal Tubular Actions of Angiotensin II

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

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Resveratrol ameliorates the cyclosporine-induced vascular and renal impairments: possible impact of the modulation of renin–angiotensin system

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2018-0753 ◽

2019 ◽

Vol 97 (12) ◽

pp. 1115-1123 ◽

Cited By ~ 2

Author(s):

Seldag Bekpinar ◽

Ece Karaca ◽

Selin Yamakoğlu ◽

F. İlkay Alp-Yıldırım ◽

Vakur Olgac ◽

...

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Renin Angiotensin System ◽

Immunosuppressive Drug ◽

Oxidative Stress Marker ◽

Converting Enzyme ◽

Angiotensin System ◽

Renin Angiotensin ◽

System Components ◽

Renal Tubular

Cyclosporine, an immunosuppressive drug, exhibits a toxic effect on renal and vascular systems. The present study investigated whether resveratrol treatment alleviates renal and vascular injury induced by cyclosporine. Cyclosporine (25 mg/kg per day, s.c.) was given for 7 days to rats either alone or in combination with resveratrol (10 mg/kg per day, i.p.). Relaxation and contraction responses of aorta were examined. Serum levels of blood urea nitrogen, creatinine, angiotensin II, and angiotensin 1-7 were measured. Histopathological examinations as well as immunostaining for 4-hydroxynonenal and nitrotyrosine were performed in the kidney. RNA expressions of renin–angiotensin system components were also measured in renal and aortic tissues. Cyclosporine decreased the endothelium-dependent relaxation and increased vascular contraction in the aorta. It caused renal tubular degeneration and increased immunostaining for 4-hydroxynonenal, an oxidative stress marker. Cyclosporine also caused upregulations of the vasoconstrictive renin–angiotensin system components in renal (angiotensin-converting enzyme) and aortic (angiotensin II type 1 receptor) tissues. Resveratrol co-treatment prevented the cyclosporine-related deteriorations. Moreover, it induced the expressions of vasodilatory effective angiotensin-converting enzyme 2 and angiotensin II type 2 receptor in aorta and kidney, respectively. We conclude that resveratrol may be effective in preventing cyclosporine-induced renal tubular degeneration and vascular dysfunction at least in part by modulating the renin–angiotensin system.

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Resveratrol prevents high glucose-induced epithelial–mesenchymal transition in renal tubular epithelial cells by inhibiting NADPH oxidase/ROS/ERK pathway

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2014.12.010 ◽

2015 ◽

Vol 402 ◽

pp. 13-20 ◽

Cited By ~ 43

Author(s):

Ting He ◽

Xu Guan ◽

Song Wang ◽

Tangli Xiao ◽

Ke Yang ◽

...

Keyword(s):

Epithelial Cells ◽

Nadph Oxidase ◽

High Glucose ◽

Epithelial Mesenchymal Transition ◽

Erk Pathway ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Mesenchymal Transition ◽

Renal Tubular

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Role of Fosinopril and Valsartan on Klotho Gene Expression Induced by Angiotensin II in Rat Renal Tubular Epithelial Cells

Kidney & Blood Pressure Research ◽

10.1159/000316703 ◽

2010 ◽

Vol 33 (3) ◽

pp. 186-192 ◽

Cited By ~ 29

Author(s):

Q. Zhou ◽

S. Lin ◽

R. Tang ◽

P. Veeraragoo ◽

W. Peng ◽

...

Keyword(s):

Gene Expression ◽

Angiotensin Ii ◽

Epithelial Cells ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Klotho Gene ◽

Renal Tubular

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INTERACTION OF NITRIC OXIDE AND TRANSFORMING GROWTH FACTOR-β1 INDUCED BY ANGIOTENSIN II AND MECHANICAL STRETCH IN RAT RENAL TUBULAR EPITHELIAL CELLS

The Journal of Urology ◽

10.1016/s0022-5347(05)67097-8 ◽

2000 ◽

Vol 164 (5) ◽

pp. 1729-1734 ◽

Cited By ~ 48

Author(s):

AKIRA MIYAJIMA ◽

JIE CHEN ◽

IRENA KIRMAN ◽

DIX P. POPPAS ◽

E. DARRACOTT VAUGHAN ◽

...

Keyword(s):

Nitric Oxide ◽

Angiotensin Ii ◽

Growth Factor ◽

Epithelial Cells ◽

Transforming Growth Factor ◽

Mechanical Stretch ◽

Transforming Growth Factor Β1 ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Renal Tubular

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Role of microRNA-29b in angiotensin II-induced epithelial-mesenchymal transition in renal tubular epithelial cells

International Journal of Molecular Medicine ◽

10.3892/ijmm.2014.1935 ◽

2014 ◽

Vol 34 (5) ◽

pp. 1381-1387 ◽

Cited By ~ 17

Author(s):

JIALIN PAN ◽

JUHONG ZHANG ◽

XINGWEI ZHANG ◽

XI ZHOU ◽

SHENGYUE LU ◽

...

Keyword(s):

Angiotensin Ii ◽

Epithelial Cells ◽

Epithelial Mesenchymal Transition ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Mesenchymal Transition ◽

Renal Tubular

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2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside Promotes Expression of the Longevity Gene Klotho

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/3128235 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 13

Author(s):

Shuang Ling ◽

Ju Duan ◽

Rongzhen Ni ◽

Jin-Wen Xu

Keyword(s):

Angiotensin Ii ◽

Vascular Endothelial Cells ◽

Functional Improvement ◽

Luciferase Reporter ◽

Kidney Medulla ◽

Spontaneously Hypertensive ◽

Mrna And Protein Expression ◽

Longevity Gene ◽

Renal Tubular

The longevity gene klotho has numerous physiological functions, such as regulating calcium and phosphorus levels, delaying senescence, improving cognition, reducing oxidative stress, and protecting vascular endothelial cells. This study tested whether 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (THSG), a small molecule with antiaging effects, regulates the expression and physiological effects of klotho. Our results showed that THSG dose-dependently increased the luciferase reporter activity of the klotho gene, reversed the decrease in mRNA and protein expression of klotho which was induced by angiotensin II in NRK-52E renal tubular epithelial cells, and increased klotho mRNA expression in the cerebral cortex, hippocampus, testis, and kidney medulla of spontaneously hypertensive rats. THSG also reduced the number of senescent cells induced by angiotensin II and improved the antioxidant capacity and enhanced the bone strength in vivo. Based on klotho’s role in promoting cognition, regulating bone metabolism, and improving renal function, the effect of THSG on klotho expression will be beneficial to the functional improvement or enhancement of the expressed organs or tissues.

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