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J Pharmacol Exp Ther. 2019 Aug;370(2):206-217. doi: 10.1124/jpet.119.258954. Epub 2019 May 22.

Knockout of Dual-Specificity Protein Phosphatase 5 Protects Against Hypertension-Induced Renal Injury.

Author information

1
Department of Pharmacology and Toxicology, University of Mississippi Medical Center. Jackson, Mississippi (C.Z., X.H., S.R.M., H.Z., S.W., Y.G., W.G., J.M.W., R.J.R., F.F.); Department of Urology, Zhongshan Hospital, Fudan University. Shanghai, China (C.Z., W.G.); and Department of Physiology, Medical College of Wisconsin. Milwaukee, Wisconsin (A.M.G.).
2
Department of Pharmacology and Toxicology, University of Mississippi Medical Center. Jackson, Mississippi (C.Z., X.H., S.R.M., H.Z., S.W., Y.G., W.G., J.M.W., R.J.R., F.F.); Department of Urology, Zhongshan Hospital, Fudan University. Shanghai, China (C.Z., W.G.); and Department of Physiology, Medical College of Wisconsin. Milwaukee, Wisconsin (A.M.G.) ffan@umc.edu.

Abstract

Dual-specificity protein phosphatase 5 (DUSP5) is a member of the tyrosine-threonine phosphatase family with the ability to dephosphorylate and inactivate extracellular signal-related kinase (ERK). The present study investigates whether knockout (KO) of Dusp5 improves renal hemodynamics and protects against hypertension-induced renal injury. The renal expression of DUSP5 was reduced, and the levels of phosphorylated (p) ERK1/2 and p-protein kinase C (PKC) α were elevated in the KO rats. KO of Dusp5 enhanced the myogenic tone of the renal afferent arteriole and interlobular artery in vitro with or without induction of deoxycorticosterone acetate-salt hypertension. Inhibition of ERK1/2 and PKC diminished the myogenic response to a greater extent in Dusp5 KO rats. Autoregulation of renal blood flow was significantly impaired in hypertensive wild-type (WT) rats but remained intact in Dusp5 KO animals. Proteinuria was markedly decreased in hypertensive KO versus WT rats. The degree of glomerular injury was reduced, and the expression of nephrin in the glomerulus was higher in hypertensive Dusp5 KO rats. Renal fibrosis and medullary protein cast formation were attenuated in hypertensive Dusp5 KO rats in association with decreased expression of monocyte chemoattractant protein 1, transforming growth factor-β1, matrix metalloproteinase (MMP) 2, and MMP9. These results indicate that KO of Dusp5 protects against hypertension-induced renal injury, at least in part, by maintaining the myogenic tone of the renal vasculature and extending the range of renal blood flow autoregulation to higher pressures, which diminish glomerular injury, protein cast formation, macrophage infiltration, and epithelial-mesenchymal transformation in the kidney. SIGNIFICANCE STATEMENT: Dual-specificity protein phosphatase 5 (DUSP5) is a tyrosine-threonine phosphatase that inactivates extracellular signal-related kinase (ERK). We previously reported that knockout (KO) of Dusp5 enhanced the myogenic response and autoregulation in the cerebral circulation. The present study investigates whether KO of DUSP5 improves renal hemodynamics and protects against hypertension-induced renal injury. Downregulation of DUSP5 enhanced the myogenic tone of renal arteriole and artery and autoregulation of renal blood flow in association with reduced proteinuria, glomerular injury, and interstitial fibrosis after the induction of hypertension. Inhibition of ERK1/2 and protein kinase C diminished the myogenic response to a greater extent in Dusp5 KO rats. These results suggest that DUSP5 might be a viable drug target for the treatment of hypertension nephropathy.

PMID:
31118214
DOI:
10.1124/jpet.119.258954
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