title: Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II-Induced Hypertension.
abstract: Angiotensin II-induced hypertension is associated with an increase in T-cell production of interleukin-17A (IL-17A). Recently, we reported that IL-17A(-/-) mice exhibit blunted hypertension, preserved natriuresis in response to a saline challenge, and decreased renal sodium hydrogen exchanger 3 expression after 2 weeks of angiotensin II infusion compared with wild-type mice. In the current study, we performed renal transporter profiling in mice deficient in IL-17A or the related isoform, IL-17F, after 4 weeks of Ang II infusion, the time when the blood pressure reduction in IL-17A(-/-) mice is most prominent. Deficiency of IL-17A abolished the activation of distal tubule transporters, specifically the sodium-chloride cotransporter and the epithelial sodium channel and protected mice from glomerular and tubular injury. In human proximal tubule (HK-2) cells, IL-17A increased sodium hydrogen exchanger 3 expression through a serum and glucocorticoid-regulated kinase 1-dependent pathway. In mouse distal convoluted tubule cells, IL-17A increased sodium-chloride cotransporter activity in a serum and glucocorticoid-regulated kinase 1/Nedd4-2-dependent pathway. In both cell types, acute treatment with IL-17A induced phosphorylation of serum and glucocorticoid-regulated kinase 1 at serine 78, and treatment with a serum and glucocorticoid-regulated kinase 1 inhibitor blocked the effects of IL-17A on sodium hydrogen exchanger 3 and sodium-chloride cotransporter. Interestingly, both HK-2 and mouse distal convoluted tubule 15 cells produce endogenous IL-17A. IL17F had little or no effect on blood pressure or renal sodium transporter abundance. These studies provide a mechanistic link by which IL-17A modulates renal sodium transport and suggest that IL-17A inhibition may improve renal function in hypertension and other autoimmune disorders.
authors.affiliation: From the Departments of Molecular Physiology and Biophysics (A.E.N., B.L.D., M.S.M.) and Microbiology, Immunology, and Pathology (J.G.), Vanderbilt University, Nashville, TN; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.A.S., L.Z., M.S.M.); Faculty of Pharmacy, Department of Pharmacology and Toxicology, Mansoura University, Mansoura, Egypt (M.A.S.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (N.V.K., A.A.M.D.); Department of Medicine, Chicago University School of Medicine, IL (B.K.); Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan (Y.I.); and Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.H.).
authors.forename: Allison E
authors.initials: AE
authors.lastname: Norlander
authors.affiliation: From the Departments of Molecular Physiology and Biophysics (A.E.N., B.L.D., M.S.M.) and Microbiology, Immunology, and Pathology (J.G.), Vanderbilt University, Nashville, TN; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.A.S., L.Z., M.S.M.); Faculty of Pharmacy, Department of Pharmacology and Toxicology, Mansoura University, Mansoura, Egypt (M.A.S.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (N.V.K., A.A.M.D.); Department of Medicine, Chicago University School of Medicine, IL (B.K.); Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan (Y.I.); and Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.H.).
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Saleh
authors.affiliation: From the Departments of Molecular Physiology and Biophysics (A.E.N., B.L.D., M.S.M.) and Microbiology, Immunology, and Pathology (J.G.), Vanderbilt University, Nashville, TN; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.A.S., L.Z., M.S.M.); Faculty of Pharmacy, Department of Pharmacology and Toxicology, Mansoura University, Mansoura, Egypt (M.A.S.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (N.V.K., A.A.M.D.); Department of Medicine, Chicago University School of Medicine, IL (B.K.); Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan (Y.I.); and Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.H.).
authors.forename: Nikhil V
authors.initials: NV
authors.lastname: Kamat
authors.affiliation: From the Departments of Molecular Physiology and Biophysics (A.E.N., B.L.D., M.S.M.) and Microbiology, Immunology, and Pathology (J.G.), Vanderbilt University, Nashville, TN; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.A.S., L.Z., M.S.M.); Faculty of Pharmacy, Department of Pharmacology and Toxicology, Mansoura University, Mansoura, Egypt (M.A.S.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (N.V.K., A.A.M.D.); Department of Medicine, Chicago University School of Medicine, IL (B.K.); Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan (Y.I.); and Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.H.).
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ko
authors.affiliation: From the Departments of Molecular Physiology and Biophysics (A.E.N., B.L.D., M.S.M.) and Microbiology, Immunology, and Pathology (J.G.), Vanderbilt University, Nashville, TN; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.A.S., L.Z., M.S.M.); Faculty of Pharmacy, Department of Pharmacology and Toxicology, Mansoura University, Mansoura, Egypt (M.A.S.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (N.V.K., A.A.M.D.); Department of Medicine, Chicago University School of Medicine, IL (B.K.); Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan (Y.I.); and Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.H.).
authors.forename: Juan
authors.initials: J
authors.lastname: Gnecco
authors.affiliation: From the Departments of Molecular Physiology and Biophysics (A.E.N., B.L.D., M.S.M.) and Microbiology, Immunology, and Pathology (J.G.), Vanderbilt University, Nashville, TN; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.A.S., L.Z., M.S.M.); Faculty of Pharmacy, Department of Pharmacology and Toxicology, Mansoura University, Mansoura, Egypt (M.A.S.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (N.V.K., A.A.M.D.); Department of Medicine, Chicago University School of Medicine, IL (B.K.); Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan (Y.I.); and Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.H.).
authors.forename: Linjue
authors.initials: L
authors.lastname: Zhu
authors.affiliation: From the Departments of Molecular Physiology and Biophysics (A.E.N., B.L.D., M.S.M.) and Microbiology, Immunology, and Pathology (J.G.), Vanderbilt University, Nashville, TN; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.A.S., L.Z., M.S.M.); Faculty of Pharmacy, Department of Pharmacology and Toxicology, Mansoura University, Mansoura, Egypt (M.A.S.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (N.V.K., A.A.M.D.); Department of Medicine, Chicago University School of Medicine, IL (B.K.); Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan (Y.I.); and Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.H.).
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Dale
authors.affiliation: From the Departments of Molecular Physiology and Biophysics (A.E.N., B.L.D., M.S.M.) and Microbiology, Immunology, and Pathology (J.G.), Vanderbilt University, Nashville, TN; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.A.S., L.Z., M.S.M.); Faculty of Pharmacy, Department of Pharmacology and Toxicology, Mansoura University, Mansoura, Egypt (M.A.S.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (N.V.K., A.A.M.D.); Department of Medicine, Chicago University School of Medicine, IL (B.K.); Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan (Y.I.); and Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.H.).
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: From the Departments of Molecular Physiology and Biophysics (A.E.N., B.L.D., M.S.M.) and Microbiology, Immunology, and Pathology (J.G.), Vanderbilt University, Nashville, TN; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.A.S., L.Z., M.S.M.); Faculty of Pharmacy, Department of Pharmacology and Toxicology, Mansoura University, Mansoura, Egypt (M.A.S.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (N.V.K., A.A.M.D.); Department of Medicine, Chicago University School of Medicine, IL (B.K.); Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan (Y.I.); and Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.H.).
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hoover
authors.affiliation: From the Departments of Molecular Physiology and Biophysics (A.E.N., B.L.D., M.S.M.) and Microbiology, Immunology, and Pathology (J.G.), Vanderbilt University, Nashville, TN; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.A.S., L.Z., M.S.M.); Faculty of Pharmacy, Department of Pharmacology and Toxicology, Mansoura University, Mansoura, Egypt (M.A.S.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (N.V.K., A.A.M.D.); Department of Medicine, Chicago University School of Medicine, IL (B.K.); Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan (Y.I.); and Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.H.).
authors.forename: Alicia A
authors.initials: AA
authors.lastname: McDonough
authors.affiliation: From the Departments of Molecular Physiology and Biophysics (A.E.N., B.L.D., M.S.M.) and Microbiology, Immunology, and Pathology (J.G.), Vanderbilt University, Nashville, TN; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (M.A.S., L.Z., M.S.M.); Faculty of Pharmacy, Department of Pharmacology and Toxicology, Mansoura University, Mansoura, Egypt (M.A.S.); Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles (N.V.K., A.A.M.D.); Department of Medicine, Chicago University School of Medicine, IL (B.K.); Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan (Y.I.); and Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA (R.S.H.).
authors.forename: Meena S
authors.initials: MS
authors.lastname: Madhur
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000503:physiopathology; D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001795:Blood Pressure Determination; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D015151:Immunoblotting; D020381:Interleukin-17 / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D049992:Sodium Chloride Symporters / Q000378:metabolism*; D064486:Solute Carrier Family 12, Member 3 / Q000378:metabolism
chemical_list: D020381:Interleukin-17; C578875:Slc12a3 protein, mouse; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D000804:Angiotensin II
keywords: angiotensin II; blood pressure; hypertension; interleukin 17; kidney