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• W3126427021 abstract "The renal collecting duct plays a critical role in setting urinary volume and composition, with principal cells transporting Na+ and K+ and intercalated cells mediating Cl− reabsorption. Published evidence implies Angiotensin II (Ang II) is a potent regulator of the collecting duct apical transport systems in response to systemic volume depletion. However, virtually nothing is known about Ang II actions on the basolateral conductance of principal and intercalated cells. Here, we combined macroscopic and single channel patch clamp recordings from freshly isolated mouse collecting ducts with biochemical and fluorescence methods to demonstrate an acute stimulation of the basolateral Cl− conductance and specifically the ClC-K2 Cl− channel by nanomolar Ang II concentrations in intercalated cells. In contrast, Ang II did not exhibit measurable effects on the basolateral conductance and on Kir4.1/5.1 potassium channel activity in principal cells. Although both Ang II receptors AT1 and AT2 are expressed in collecting duct cells, we show that AT1 receptors were essential for stimulatory actions of Ang II on ClC-K2. Moreover, AT1R−/− mice had decreased renal ClC-K2 expression. We further demonstrated that activation of NADPH oxidases is the major signaling pathway downstream of Ang II-AT1R that leads to stimulation of ClC-K2. Treatment of freshly isolated collecting ducts with Ang II led to production of reactive oxygen species on the same timescale as single channel ClC-K2 activation. Overall, we propose that Ang II-dependent regulation of ClC-K2 in intercalated cells is instrumental for stimulation of Cl− reabsorption by the collecting duct, particularly during hypovolemic states. The renal collecting duct plays a critical role in setting urinary volume and composition, with principal cells transporting Na+ and K+ and intercalated cells mediating Cl− reabsorption. Published evidence implies Angiotensin II (Ang II) is a potent regulator of the collecting duct apical transport systems in response to systemic volume depletion. However, virtually nothing is known about Ang II actions on the basolateral conductance of principal and intercalated cells. Here, we combined macroscopic and single channel patch clamp recordings from freshly isolated mouse collecting ducts with biochemical and fluorescence methods to demonstrate an acute stimulation of the basolateral Cl− conductance and specifically the ClC-K2 Cl− channel by nanomolar Ang II concentrations in intercalated cells. In contrast, Ang II did not exhibit measurable effects on the basolateral conductance and on Kir4.1/5.1 potassium channel activity in principal cells. Although both Ang II receptors AT1 and AT2 are expressed in collecting duct cells, we show that AT1 receptors were essential for stimulatory actions of Ang II on ClC-K2. Moreover, AT1R−/− mice had decreased renal ClC-K2 expression. We further demonstrated that activation of NADPH oxidases is the major signaling pathway downstream of Ang II-AT1R that leads to stimulation of ClC-K2. Treatment of freshly isolated collecting ducts with Ang II led to production of reactive oxygen species on the same timescale as single channel ClC-K2 activation. Overall, we propose that Ang II-dependent regulation of ClC-K2 in intercalated cells is instrumental for stimulation of Cl− reabsorption by the collecting duct, particularly during hypovolemic states. Hypertension is one of the major causes of morbidity and mortality affecting approximately 46% of US adults, with blood pressure in 50% of hypertensive individuals exhibiting a salt-sensitive pattern (1Reboussin D.M. Allen N.B. Griswold M.E. Guallar E. Hong Y. Lackland D.T. Miller 3rd, E.P.R. Polonsky T. Thompson-Paul A.M. Vupputuri S. Systematic review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.Circulation. 2018; 138: e595-e616Crossref PubMed Scopus (31) Google Scholar, 2Kotchen T.A. Cowley Jr., A.W. Frohlich E.D. Salt in health and disease--a delicate balance.N. Engl. J. Med. 2013; 368: 1229-1237Crossref PubMed Scopus (90) Google Scholar). Elevated blood pressure is commonly caused by expansion of the circulating volume due to salt retention by the kidney (3Meneton P. Jeunemaitre X. de Wardener H.E. MacGregor G.A. Links between dietary salt intake, renal salt handling, blood pressure, and cardiovascular diseases.Physiol. Rev. 2005; 85: 679-715Crossref PubMed Scopus (514) Google Scholar). Variations in dietary salt intake regulate transport in the renal collecting duct via the renin–angiotensin–aldosterone system to shape urinary NaCl excretion and to maintain circulating volume (4Pratt J.H. Central role for ENaC in development of hypertension.J. Am. Soc. Nephrol. 2005; 16: 3154-3159Crossref PubMed Scopus (74) Google Scholar, 5Bhalla V. Hallows K.R. Mechanisms of ENaC regulation and clinical implications.J. Am. Soc. Nephrol. 2008; 19: 1845-1854Crossref PubMed Scopus (178) Google Scholar). The collecting duct is composed of electrically uncoupled principal and intercalated cells (6Pearce D. Soundararajan R. Trimpert C. Kashlan O.B. Deen P.M. Kohan D.E. Collecting duct principal cell transport processes and their regulation.Clin. J. Am. Soc. Nephrol. 2014; 10: 135-146Crossref PubMed Scopus (152) Google Scholar, 7Roy A. Al-bataineh M.M. Pastor-Soler N.M. Collecting duct intercalated cell function and regulation.Clin. J. Am. Soc. Nephrol. 2015; 10: 305-324Crossref PubMed Scopus (105) Google Scholar). Principal cells perform electrogenic Na+ reabsorption via the epithelial Na+ channel (ENaC) localized to the apical membrane and the Na+/K+ ATPase on the basolateral membrane (5Bhalla V. Hallows K.R. Mechanisms of ENaC regulation and clinical implications.J. Am. Soc. Nephrol. 2008; 19: 1845-1854Crossref PubMed Scopus (178) Google Scholar, 8Masilamani S. Kim G.H. Mitchell C. Wade J.B. Knepper M.A. Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney.J. Clin. Invest. 1999; 104: R19-R23Crossref PubMed Scopus (596) Google Scholar, 9Staruschenko A. Regulation of transport in the connecting tubule and cortical collecting duct.Compr. Physiol. 2012; 2: 1541-1584Crossref PubMed Scopus (77) Google Scholar). Intercalated cells are essential for maintaining acid–base balance by secreting H+ via the apical V-ATPase (A-type) and HCO3− via pendrin (SLC26A4) in the B-type (7Roy A. Al-bataineh M.M. Pastor-Soler N.M. Collecting duct intercalated cell function and regulation.Clin. J. Am. Soc. Nephrol. 2015; 10: 305-324Crossref PubMed Scopus (105) Google Scholar). In addition, both A- and B-types have the capacity to reabsorb Cl− even when ENaC activity is blocked with amiloride (10Pech V. Kim Y.H. Weinstein A.M. Everett L.A. Pham T.D. Wall S.M. Angiotensin II increases chloride absorption in the cortical collecting duct in mice through a pendrin-dependent mechanism.Am. J. Physiol. Renal Physiol. 2007; 292: F914-F920Crossref PubMed Scopus (91) Google Scholar). Since both types of intercalated cells are involved, it is viewed that Cl− reabsorption could occur with little or no changes in net acid or base secretion (11Wall S.M. Weinstein A.M. Cortical distal nephron Cl- transport in volume homeostasis and blood pressure regulation.Am. J. Physiol. Renal Physiol. 2013; 305: F427-F438Crossref PubMed Scopus (43) Google Scholar). The long-standing paradigm suggests that Ang II-driven secretion of the mineralocorticoid aldosterone from adrenal gland leads to upregulation of the ENaC-dependent Na+ reabsorption in the collecting duct during the volume-depleted states (6Pearce D. Soundararajan R. Trimpert C. Kashlan O.B. Deen P.M. Kohan D.E. Collecting duct principal cell transport processes and their regulation.Clin. J. Am. Soc. Nephrol. 2014; 10: 135-146Crossref PubMed Scopus (152) Google Scholar). However, cumulative evidence demonstrates aldosterone-independent direct actions of Ang II on Na+ and Cl− transport in the collecting duct during variations in salt intake and in the pathophysiology of Ang-dependent hypertension (10Pech V. Kim Y.H. Weinstein A.M. Everett L.A. Pham T.D. Wall S.M. Angiotensin II increases chloride absorption in the cortical collecting duct in mice through a pendrin-dependent mechanism.Am. J. Physiol. Renal Physiol. 2007; 292: F914-F920Crossref PubMed Scopus (91) Google Scholar, 12Peti-Peterdi J. Warnock D.G. Bell P.D. Angiotensin II directly stimulates ENaC activity in the cortical collecting duct via AT1 receptors.J. Am. Soc. Nephrol. 2002; 13: 1131-1135Crossref PubMed Scopus (245) Google Scholar, 13Mamenko M. Zaika O. Prieto M.C. Jensen V.B. Doris P.A. Navar L.G. Pochynyuk O. Chronic angiotensin II infusion drives extensive aldosterone-independent epithelial Na+ channel activation.Hypertension. 2013; 62: 1111-1122Crossref PubMed Scopus (44) Google Scholar, 14Mamenko M. Zaika O. Ilatovskaya D.V. Staruschenko A. Pochynyuk O. Angiotensin II increases activity of the epithelial Na+ channel (ENaC) in distal nephron additively to aldosterone.J. Biol. Chem. 2012; 287: 660-671Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). In fact, kidneys have substantial capacity to locally produce Ang II. In the experimental animal models of Ang II-induced hypertension (15Gonzalez-Villalobos R.A. Satou R. Ohashi N. Semprun-Prieto L.C. Katsurada A. Kim C. Upchurch G.M. Prieto M.C. Kobori H. Navar L.G. Intrarenal mouse renin-angiotensin system during ANG II-induced hypertension and ACE inhibition.Am. J. Physiol. Renal Physiol. 2010; 298: F150-F157Crossref PubMed Scopus (57) Google Scholar, 16Gonzalez-Villalobos R.A. Seth D.M. Satou R. Horton H. Ohashi N. Miyata K. Katsurada A. Tran D.V. Kobori H. Navar L.G. Intrarenal angiotensin II and angiotensinogen augmentation in chronic angiotensin II-infused mice.Am. J. Physiol. Renal Physiol. 2008; 295: F772-F779Crossref PubMed Scopus (80) Google Scholar), intrarenal Ang II levels become much higher (over 100-fold) than those in plasma (17Navar L.G. Prieto M.C. Satou R. Kobori H. Intrarenal angiotensin II and its contribution to the genesis of chronic hypertension.Curr. Opin. Pharmacol. 2011; 11: 180-186Crossref PubMed Scopus (117) Google Scholar, 18Navar L.G. Lewis L. Hymel A. Braam B. Mitchell K.D. Tubular fluid concentrations and kidney contents of angiotensins I and II in anesthetized rats.J. Am. Soc. Nephrol. 1994; 5: 1153-1158Crossref PubMed Google Scholar, 19Siragy H.M. Howell N.L. Ragsdale N.V. Carey R.M. Renal interstitial fluid angiotensin. Modulation by anesthesia, epinephrine, sodium depletion, and renin inhibition.Hypertension. 1995; 25: 1021-1024Crossref PubMed Scopus (121) Google Scholar). Ang II binds to AT1 and AT2 receptors to exert its numerous physiological actions. Activation of AT1R promotes proliferation, vasoconstriction, antinatriuresis, salt appetite, etc. (20Zaman M.A. Oparil S. Calhoun D.A. Drugs targeting the renin-angiotensin-aldosterone system.Nat. Rev. Drug Discov. 2002; 1: 621-636Crossref PubMed Scopus (330) Google Scholar, 21Seva P.B. van der L.N. Verdonk K. Roks A.J. Hoorn E.J. Danser A.H. Key developments in renin-angiotensin-aldosterone system inhibition.Nat. Rev. Nephrol. 2012; 9: 26-36Crossref PubMed Scopus (69) Google Scholar, 22Kaschina E. Unger T. Angiotensin AT1/AT2 receptors: Regulation, signalling and function.Blood Press. 2003; 12: 70-88Crossref PubMed Scopus (333) Google Scholar, 23Crowley S.D. Coffman T.M. Recent advances involving the renin-angiotensin system.Exp. Cell Res. 2012; 318: 1049-1056Crossref PubMed Scopus (108) Google Scholar, 24Berry C. Touyz R. Dominiczak A.F. Webb R.C. Johns D.G. Angiotensin receptors: Signaling, vascular pathophysiology, and interactions with ceramide.Am. J. Physiol. Heart Circ. Physiol. 2001; 281: H2337-H2365Crossref PubMed Google Scholar). AT2R antagonizes the actions of AT1R resulting in vasodilation, natriuresis, and prostaglandin release (20Zaman M.A. Oparil S. Calhoun D.A. Drugs targeting the renin-angiotensin-aldosterone system.Nat. Rev. Drug Discov. 2002; 1: 621-636Crossref PubMed Scopus (330) Google Scholar, 22Kaschina E. Unger T. Angiotensin AT1/AT2 receptors: Regulation, signalling and function.Blood Press. 2003; 12: 70-88Crossref PubMed Scopus (333) Google Scholar, 25Carey R.M. Wang Z.Q. Siragy H.M. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function.Hypertension. 2000; 35: 155-163Crossref PubMed Google Scholar). Both AT1R (most abundantly AT1aR isoform in mice) and AT2R are expressed at the apical and basolateral sides of the collecting duct cells, although AT2R expression is considerably lower (25Carey R.M. Wang Z.Q. Siragy H.M. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function.Hypertension. 2000; 35: 155-163Crossref PubMed Google Scholar, 26Miyata N. Park F. Li X.F. Cowley Jr., A.W. Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney.Am. J. Physiol. 1999; 277: F437-F446PubMed Google Scholar, 27Ozono R. Wang Z.Q. Moore A.F. Inagami T. Siragy H.M. Carey R.M. Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney.Hypertension. 1997; 30: 1238-1246Crossref PubMed Scopus (274) Google Scholar). Chronic Ang II infusion stimulates ENaC activity well above the physiological range of regulation (13Mamenko M. Zaika O. Prieto M.C. Jensen V.B. Doris P.A. Navar L.G. Pochynyuk O. Chronic angiotensin II infusion drives extensive aldosterone-independent epithelial Na+ channel activation.Hypertension. 2013; 62: 1111-1122Crossref PubMed Scopus (44) Google Scholar), which cannot be effectively inhibited by mineralocorticoid receptor blockade (28Ortiz R.M. Graciano M.L. Seth D. Awayda M.S. Navar L.G. Aldosterone receptor antagonism exacerbates intrarenal angiotensin II augmentation in ANG II-dependent hypertension.Am. J. Physiol. Renal Physiol. 2007; 293: F139-F147Crossref PubMed Scopus (33) Google Scholar). Ang II also increases Cl− reabsorption, in part by stimulating apically localized HCO3−/Cl− exchanger pendrin in B-type intercalated cells (10Pech V. Kim Y.H. Weinstein A.M. Everett L.A. Pham T.D. Wall S.M. Angiotensin II increases chloride absorption in the cortical collecting duct in mice through a pendrin-dependent mechanism.Am. J. Physiol. Renal Physiol. 2007; 292: F914-F920Crossref PubMed Scopus (91) Google Scholar). At the same time, the actions of Ang II on the basolateral conductance of the collecting duct cells are not known. Basolateral electrical conductance of the collecting duct principal cells is almost exclusively K+ selective (29Zaika O. Palygin O. Tomilin V. Mamenko M. Staruschenko A. Pochynyuk O. Insulin and IGF-1 activate Kir4.1/5.1 channels in cortical collecting duct principal cells to control basolateral membrane voltage.Am. J. Physiol. Renal Physiol. 2016; 310: F311-F321Crossref PubMed Scopus (25) Google Scholar, 30Muto S. Yasoshima K. Yoshitomi K. Imai M. Asano Y. Electrophysiological identification of alpha- and beta-intercalated cells and their distribution along the rabbit distal nephron segments.J. Clin. Invest. 1990; 86: 1829-1839Crossref PubMed Scopus (93) Google Scholar). The most prevalent heteromeric inward rectifying Kir4.1/5.1 40 pS potassium channel is essential for K+ recycling to set up a strong hyperpolarizing resting potential on the basolateral membrane around −70 mV to establish a favorable driving force for ENaC-mediated Na+ reabsorption (29Zaika O. Palygin O. Tomilin V. Mamenko M. Staruschenko A. Pochynyuk O. Insulin and IGF-1 activate Kir4.1/5.1 channels in cortical collecting duct principal cells to control basolateral membrane voltage.Am. J. Physiol. Renal Physiol. 2016; 310: F311-F321Crossref PubMed Scopus (25) Google Scholar, 31Lachheb S. Cluzeaud F. Bens M. Genete M. Hibino H. Lourdel S. Kurachi Y. Vandewalle A. Teulon J. Paulais M. Kir4.1/Kir5.1 channel forms the major K+ channel in the basolateral membrane of mouse renal collecting duct principal cells.Am. J. Physiol. Renal Physiol. 2008; 294: F1398-F1407Crossref PubMed Scopus (93) Google Scholar). Kir4.1/5.1 is also expressed in the upstream segments, most notably the distal convoluted tubule, to control NaCl reabsorption via thiazide-sensitive NCC cotransporter (32Terker A.S. Zhang C. McCormick J.A. Lazelle R.A. Zhang C. Meermeier N.P. Siler D.A. Park H.J. Fu Y. Cohen D.M. Weinstein A.M. Wang W.H. Yang C.L. Ellison D.H. Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride.Cell Metab. 2015; 21: 39-50Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 33Cuevas C.A. Su X.T. Wang M.X. Terker A.S. Lin D.H. McCormick J.A. Yang C.L. Ellison D.H. Wang W.H. Potassium sensing by renal distal tubules requires Kir4.1.J. Am. Soc. Nephrol. 2017; 28: 1814-1825Crossref PubMed Scopus (91) Google Scholar). Loss-of-function mutations in the KCNJ10 gene encoding Kir4.1 subunit result in EAST/SeSAME syndrome, a complex electrolyte imbalance disorder manifested as hypotension, natriuresis, hypocalciuria, hypomagnesemia, and hypokalemic metabolic alkalosis (34Bockenhauer D. Feather S. Stanescu H.C. Bandulik S. Zdebik A.A. Reichold M. Tobin J. Lieberer E. Sterner C. Landoure G. Arora R. Sirimanna T. Thompson D. Cross J.H. van't Hoff W. et al.Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations.N. Engl. J. Med. 2009; 360: 1960-1970Crossref PubMed Scopus (399) Google Scholar, 35Scholl U.I. Choi M. Liu T. Ramaekers V.T. Hausler M.G. Grimmer J. Tobe S.W. Farhi A. Nelson-Williams C. Lifton R.P. Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10.Proc. Natl. Acad. Sci. U. S. A. 2009; 106: 5842-5847Crossref PubMed Scopus (333) Google Scholar). Consistently, Kcnj16 deletion encoding the Kir5.1 subunit ameliorated the development of salt-sensitive hypertension in Dahl SS rats (36Palygin O. Levchenko V. Ilatovskaya D.V. Pavlov T.S. Pochynyuk O.M. Jacob H.J. Geurts A.M. Hodges M.R. Staruschenko A. Essential role of Kir5.1 channels in renal salt handling and blood pressure control.JCI Insight. 2017; 2e92331Crossref PubMed Scopus (44) Google Scholar). Intercalated cells of the collecting duct do not express Na+/K+ ATPase and have no electrogenic basolateral potassium conductance (7Roy A. Al-bataineh M.M. Pastor-Soler N.M. Collecting duct intercalated cell function and regulation.Clin. J. Am. Soc. Nephrol. 2015; 10: 305-324Crossref PubMed Scopus (105) Google Scholar, 30Muto S. Yasoshima K. Yoshitomi K. Imai M. Asano Y. Electrophysiological identification of alpha- and beta-intercalated cells and their distribution along the rabbit distal nephron segments.J. Clin. Invest. 1990; 86: 1829-1839Crossref PubMed Scopus (93) Google Scholar). Instead, activity of the ClC-K2 chloride channel determines basolateral Cl− transport and sets the resting potential around −20 mV (37Hennings J.C. Andrini O. Picard N. Paulais M. Huebner A.K. Cayuqueo I.K. Bignon Y. Keck M. Corniere N. Bohm D. Jentsch T.J. Chambrey R. Teulon J. Hubner C.A. Eladari D. The ClC-K2 chloride channel is critical for salt handling in the distal nephron.J. Am. Soc. Nephrol. 2017; 28: 209-217Crossref PubMed Scopus (62) Google Scholar, 38Nissant A. Paulais M. Lachheb S. Lourdel S. Teulon J. Similar chloride channels in the connecting tubule and cortical collecting duct of the mouse kidney.Am. J. Physiol. Renal Physiol. 2006; 290: F1421-F1429Crossref PubMed Scopus (40) Google Scholar). Similarly to Kir4.1/5.1, ClC-K2 is also expressed in the distal nephron segments, namely, the thick ascending limb and distal convoluted tubule (37Hennings J.C. Andrini O. Picard N. Paulais M. Huebner A.K. Cayuqueo I.K. Bignon Y. Keck M. Corniere N. Bohm D. Jentsch T.J. Chambrey R. Teulon J. Hubner C.A. Eladari D. The ClC-K2 chloride channel is critical for salt handling in the distal nephron.J. Am. Soc. Nephrol. 2017; 28: 209-217Crossref PubMed Scopus (62) Google Scholar, 39Lourdel S. Paulais M. Marvao P. Nissant A. Teulon J. A chloride channel at the basolateral membrane of the distal-convoluted tubule: A candidate ClC-K channel.J. Gen. Physiol. 2003; 121: 287-300Crossref PubMed Scopus (47) Google Scholar). Inactivating mutations in the CLCNKB gene (encoding ClC-Kb, human version of ClC-K2) underlie Bartter’s syndrome type III associated with hypotension, hypochloremia, and metabolic alkalosis (40Simon D.B. Bindra R.S. Mansfield T.A. Nelson-Williams C. Mendonca E. Stone R. Schurman S. Nayir A. Alpay H. Bakkaloglu A. Rodriguez-Soriano J. Morales J.M. Sanjad S.A. Taylor C.M. Pilz D. et al.Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III.Nat. Genet. 1997; 17: 171-178Crossref PubMed Scopus (735) Google Scholar, 41Andrini O. Keck M. Briones R. Lourdel S. Vargas-Poussou R. Teulon J. ClC-K chloride channels: Emerging pathophysiology of Bartter syndrome type 3.Am. J. Physiol. Renal Physiol. 2015; 308: F1324-F1334Crossref PubMed Scopus (35) Google Scholar, 42Birkenhager R. Otto E. Schurmann M.J. Vollmer M. Ruf E.M. Maier-Lutz I. Beekmann F. Fekete A. Omran H. Feldmann D. Milford D.V. Jeck N. Konrad M. Landau D. Knoers N.V. et al.Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure.Nat. Genet. 2001; 29: 310-314Crossref PubMed Scopus (403) Google Scholar). Of note, Kir4.1/5.1 and ClC-K2 are expressed in all cells of the thick ascending limb and distal convoluted tubule, whereas they are separated to principal and intercalated cells of the collecting duct, respectively (43Kobayashi K. Uchida S. Mizutani S. Sasaki S. Marumo F. Intrarenal and cellular localization of CLC-K2 protein in the mouse kidney.J. Am. Soc. Nephrol. 2001; 12: 1327-1334Crossref PubMed Google Scholar). It is possible that such mosaic architecture of the collecting duct allows independent cell type–specific regulation of Na+ and Cl− transport by endocrine signals, such as Ang II. The major focus of the current study was to explore the functional consequences and uncover the molecular mechanisms of Ang II actions on Kir4.1./5.1 potassium and ClC-K2 chloride conductance in native collecting duct cells. The renal collecting duct is a heterogeneous nephron segment containing electrically uncoupled principal and intercalated cells exhibiting different morphology and physiological functions (6Pearce D. Soundararajan R. Trimpert C. Kashlan O.B. Deen P.M. Kohan D.E. Collecting duct principal cell transport processes and their regulation.Clin. J. Am. Soc. Nephrol. 2014; 10: 135-146Crossref PubMed Scopus (152) Google Scholar, 7Roy A. Al-bataineh M.M. Pastor-Soler N.M. Collecting duct intercalated cell function and regulation.Clin. J. Am. Soc. Nephrol. 2015; 10: 305-324Crossref PubMed Scopus (105) Google Scholar). We first used patch clamp electrophysiology in freshly isolated collecting duct to assess Ang II actions on the basolateral conductance in principal and intercalated cells. Since electrical conductance of the apical membrane is much lower than the conductance of the basolateral membrane for both cell types (29Zaika O. Palygin O. Tomilin V. Mamenko M. Staruschenko A. Pochynyuk O. Insulin and IGF-1 activate Kir4.1/5.1 channels in cortical collecting duct principal cells to control basolateral membrane voltage.Am. J. Physiol. Renal Physiol. 2016; 310: F311-F321Crossref PubMed Scopus (25) Google Scholar, 44Gray D.A. Frindt G. Zhang Y.Y. Palmer L.G. Basolateral K+ conductance in principal cells of rat CCD.Am. J. Physiol. Renal Physiol. 2005; 288: F493-F504Crossref PubMed Scopus (35) Google Scholar), the changes in macroscopic whole cell current chiefly reflect alterations in the electrical conductance of the basolateral membrane. Figure 1A shows representative macroscopic currents from aquaporin type 2 (AQP2)-positive principal cells of freshly isolated collecting ducts before and after application of Ang II (500 nM for 3 min). The respective current–voltage relations demonstrate notable inward rectification and reversal around −70 mV (Fig. 1B), which is characteristic of the K+-selective conductance via Kir4.1/5.1 channel, as we and others have reported previously (29Zaika O. Palygin O. Tomilin V. Mamenko M. Staruschenko A. Pochynyuk O. Insulin and IGF-1 activate Kir4.1/5.1 channels in cortical collecting duct principal cells to control basolateral membrane voltage.Am. J. Physiol. Renal Physiol. 2016; 310: F311-F321Crossref PubMed Scopus (25) Google Scholar, 31Lachheb S. Cluzeaud F. Bens M. Genete M. Hibino H. Lourdel S. Kurachi Y. Vandewalle A. Teulon J. Paulais M. Kir4.1/Kir5.1 channel forms the major K+ channel in the basolateral membrane of mouse renal collecting duct principal cells.Am. J. Physiol. Renal Physiol. 2008; 294: F1398-F1407Crossref PubMed Scopus (93) Google Scholar). However, we did not observe any significant changes in the amplitude of the Kir4.1/5.1-mediated K+ current in principal cells after treatment with Ang II (Fig. 1, A and B). The AQP2-negative intercalated cells exhibited anion-selective conductance with a reversal around −20 mV (Fig. 1, C and D), which is mediated by the ClC-K2 Cl− channel on the basolateral membrane (45Tomilin V.N. Zaika O. Subramanya A.R. Pochynyuk O. Dietary K+ and Cl- independently regulate basolateral conductance in principal and intercalated cells of the collecting duct.Pflugers Arch. 2018; 470: 339-353Crossref PubMed Scopus (12) Google Scholar). Of importance, application of Ang II (500 nM for 3 min) significantly increased the amplitude of the Cl−-dependent current by almost 2-fold. These results show that Ang II increases the basolateral conductance specifically in the intercalated cells of the collecting duct. We next assessed the effects of Ang II on the basolateral conductance of collecting duct cells at the single channel level. As shown in the representative experiment (Fig. 2A) and the summary graph (Fig. 2B), application of Ang II (500 nM) did not affect the open probability of the 40 pS Kir4.1/5.1 channel, the dominant K+ channel in the basolateral membrane of the principal cells (29Zaika O. Palygin O. Tomilin V. Mamenko M. Staruschenko A. Pochynyuk O. Insulin and IGF-1 activate Kir4.1/5.1 channels in cortical collecting duct principal cells to control basolateral membrane voltage.Am. J. Physiol. Renal Physiol. 2016; 310: F311-F321Crossref PubMed Scopus (25) Google Scholar, 31Lachheb S. Cluzeaud F. Bens M. Genete M. Hibino H. Lourdel S. Kurachi Y. Vandewalle A. Teulon J. Paulais M. Kir4.1/Kir5.1 channel forms the major K+ channel in the basolateral membrane of mouse renal collecting duct principal cells.Am. J. Physiol. Renal Physiol. 2008; 294: F1398-F1407Crossref PubMed Scopus (93) Google Scholar). In contrast, Ang II significantly increased the open probability of the 10 pS ClC-K2 channel (46Zaika O. Mamenko M. Boukelmoune N. Pochynyuk O. IGF-1 and insulin exert opposite actions on ClC-K2 activity in the cortical collecting ducts.Am. J. Physiol. Renal Physiol. 2015; 308: F39-F48Crossref PubMed Scopus (16) Google Scholar) in a reversible manner in intercalated cells (Fig. 3A). As summarized in Figure 3B, the mean open probability was 0.32 ± 0.06, 0.52 ± 0.05, and 0.31 ± 0.06 in the control, after Ang II application, and following washout with control medium, respectively. Ang II increased the ClC-K2 open probability in a dose-dependent manner. As shown in Figure 3C, Ang II concentrations higher than 5 nM exhibited a significant stimulatory effect on single channel ClC-K2 activity. It is worth mentioning that similar levels of interstitial Ang II were reported in the kidney (18Navar L.G. Lewis L. Hymel A. Braam B. Mitchell K.D. Tubular fluid concentrations and kidney contents of angiotensins I and II in anesthetized rats.J. Am. Soc. Nephrol. 1994; 5: 1153-1158Crossref PubMed Google Scholar) arguing for the physiological relevance of Ang II actions on ClC-K2–dependent Cl− conductance in the intercalated cells.Figure 3Ang II stimulates activity of ClC-K2 channel in a dose-dependent manner. A, representative continuous current trace from a cell-attached patch monitoring activity of basolateral 10 pS ClC-K2 chloride channels in an intercalated cell in a freshly isolated collecting duct in the control, upon application of 500 nM Ang II (shown with a line on top) and following washout with control medium. The patch was clamped to −Vp = −60 mV; “c” denotes closed nonconducting state. Areas (1, control) and (2, Ang II) are shown below at an expanded timescale. B, summary graph of changes in ClC-K2 open probability (Po) upon treatment with 500 nM Ang II from paired patch clamp experiments similar to that shown in (A). C, summary graph of average changes in ClC-K2 Po in individual cells upon application of different Ang II concentrations. ∗ - significant increase (p < 0.05) versus control (one-way ANOVA). Collecting ducts from at least three different mice were used for each set of experiments.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Expression of both AT1 and AT2 receptors was reported in the collecting duct cells (25Carey R.M. Wang Z.Q. Siragy H.M. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function.Hypertension. 2000; 35: 155-163Crossref PubMed Google Scholar, 26Miyata N. Park F. Li X.F. Cowley Jr., A.W. Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney.Am. J. Physiol. 1999; 277: F437-F446PubMed Google Scholar, 27Ozono R. Wang Z.Q. Moore A.F. Inagami T. Siragy H.M. Carey R.M. Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney.Hype" @default.
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• W3126427021 title "Angiotensin II increases activity of the ClC-K2 Cl− channel in collecting duct intercalated cells by stimulating production of reactive oxygen species" @default.
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