Activation of the Hypoxia-Inducible Factor Pathway Inhibits Epithelial Sodium Channel-Mediated Sodium Transport in Collecting Duct Principal Cells.
Journal
Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836
Informations de publication
Date de publication:
01 12 2021
01 12 2021
Historique:
received:
13
01
2021
accepted:
05
09
2021
pubmed:
8
10
2021
medline:
8
2
2023
entrez:
7
10
2021
Statut:
ppublish
Résumé
Active sodium reabsorption is the major factor influencing renal oxygen consumption and production of reactive oxygen species (ROS). Increased sodium reabsorption uses more oxygen, which may worsen medullary hypoxia and produce more ROS via enhanced mitochondrial ATP synthesis. Both mechanisms may activate the hypoxia-inducible factor (HIF) pathway. Because the collecting duct is exposed to low oxygen pressure and variations of active sodium transport, we assessed whether the HIF pathway controls epithelial sodium channel (ENaC)-dependent sodium transport. We investigated HIF's effect on ENaC expression in mpkCCD cl4 cells (a model of collecting duct principal cells) using real-time PCR and western blot and ENaC activity by measuring amiloride-sensitive current. We also assessed the effect of hypoxia and sodium intake on abundance of kidney sodium transporters in wild-type and inducible kidney tubule-specific Hif1α knockout mice. In cultured cells, activation of the HIF pathway by dimethyloxalylglycine or hypoxia inhibited sodium transport and decreased expression of β ENaC and γ ENaC, as well as of Na,K-ATPase. HIF1 α silencing increased β ENaC and γ ENaC expression and stimulated sodium transport. A constitutively active mutant of HIF1 α produced the opposite effect. Aldosterone and inhibition of the mitochondrial respiratory chain slowly activated the HIF pathway, suggesting that ROS may also activate HIF. Decreased γ ENaC abundance induced by hypoxia in normal mice was abolished in Hif1α knockout mice. Similarly, Hif1α knockout led to increased γ ENaC abundance under high sodium intake. This study reveals that γ ENaC expression and activity are physiologically controlled by the HIF pathway, which may represent a negative feedback mechanism to preserve oxygenation and/or prevent excessive ROS generation under increased sodium transport.
Sections du résumé
BACKGROUND
Active sodium reabsorption is the major factor influencing renal oxygen consumption and production of reactive oxygen species (ROS). Increased sodium reabsorption uses more oxygen, which may worsen medullary hypoxia and produce more ROS via enhanced mitochondrial ATP synthesis. Both mechanisms may activate the hypoxia-inducible factor (HIF) pathway. Because the collecting duct is exposed to low oxygen pressure and variations of active sodium transport, we assessed whether the HIF pathway controls epithelial sodium channel (ENaC)-dependent sodium transport.
METHODS
We investigated HIF's effect on ENaC expression in mpkCCD cl4 cells (a model of collecting duct principal cells) using real-time PCR and western blot and ENaC activity by measuring amiloride-sensitive current. We also assessed the effect of hypoxia and sodium intake on abundance of kidney sodium transporters in wild-type and inducible kidney tubule-specific Hif1α knockout mice.
RESULTS
In cultured cells, activation of the HIF pathway by dimethyloxalylglycine or hypoxia inhibited sodium transport and decreased expression of β ENaC and γ ENaC, as well as of Na,K-ATPase. HIF1 α silencing increased β ENaC and γ ENaC expression and stimulated sodium transport. A constitutively active mutant of HIF1 α produced the opposite effect. Aldosterone and inhibition of the mitochondrial respiratory chain slowly activated the HIF pathway, suggesting that ROS may also activate HIF. Decreased γ ENaC abundance induced by hypoxia in normal mice was abolished in Hif1α knockout mice. Similarly, Hif1α knockout led to increased γ ENaC abundance under high sodium intake.
CONCLUSIONS
This study reveals that γ ENaC expression and activity are physiologically controlled by the HIF pathway, which may represent a negative feedback mechanism to preserve oxygenation and/or prevent excessive ROS generation under increased sodium transport.
Identifiants
pubmed: 34615708
pii: 00001751-202112000-00020
doi: 10.1681/ASN.2021010046
pmc: PMC8638392
doi:
Substances chimiques
Epithelial Sodium Channels
0
Sodium-Potassium-Exchanging ATPase
EC 7.2.2.13
Reactive Oxygen Species
0
Sodium
9NEZ333N27
Sodium, Dietary
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3130-3145Informations de copyright
Copyright © 2021 by the American Society of Nephrology.
Références
Weidemann A, Bernhardt WM, Klanke B, Daniel C, Buchholz B, Câmpean V, et al.: HIF activation protects from acute kidney injury. J Am Soc Nephrol 19: 486–494, 2008
Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, et al.: Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 117: 3810–3820, 2007
Kojima I, Tanaka T, Inagi R, Kato H, Yamashita T, Sakiyama A, et al.: Protective role of hypoxia-inducible factor-2 α against ischemic damage and oxidative stress in the kidney. J Am Soc Nephrol 18: 1218–1226, 2007
Nordquist L, Friederich-Persson M, Fasching A, Liss P, Shoji K, Nangaku M, et al.: Activation of hypoxia-inducible factors prevents diabetic nephropathy. J Am Soc Nephrol 26: 328–338, 2015
Lübbers DW, Baumgärtl H: Heterogeneities and profiles of oxygen pressure in brain and kidney as examples of the pO 2 distribution in the living tissue. Kidney Int 51: 372–380, 1997
Haase VH: Oxygen sensors as therapeutic targets in kidney disease. Nephrol Ther 13[Suppl 1]: S29–S34, 2017
Hu C-J, Wang L-Y, Chodosh LA, Keith B, Simon MC: Differential roles of hypoxia-inducible factor 1 α (HIF-1 α ) and HIF-2 α in hypoxic gene regulation. Mol Cell Biol 23: 9361–9374, 2003
Hill P, Shukla D, Tran MG, Aragones J, Cook HT, Carmeliet P, et al.: Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury. J Am Soc Nephrol 19: 39–46, 2008
Singh P, Blantz RC, Rosenberger C, Gabbai FB, Schoeb TR, Thomson SC: Aberrant tubuloglomerular feedback and HIF-1 α confer resistance to ischemia after subtotal nephrectomy. J Am Soc Nephrol 23: 483–493, 2012
Nlandu Khodo S, Dizin E, Sossauer G, Szanto I, Martin PY, Feraille E, et al.: NADPH-oxidase 4 protects against kidney fibrosis during chronic renal injury. J Am Soc Nephrol 23: 1967–1976, 2012
Heuett WJ, Periwal V: Autoregulation of free radicals via uncoupling protein control in pancreatic β -cell mitochondria. Biophys J 98: 207–217, 2010
Boveris A: Mitochondrial production of superoxide radical and hydrogen peroxide. Adv Exp Med Biol 78: 67–82, 1977
Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu S-S: Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 287: C817–C833, 2004
Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, et al.: Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1 α during hypoxia: a mechanism of O 2 sensing. J Biol Chem 275: 25130–25138, 2000
Gamba G, Miyanoshita A, Lombardi M, Lytton J, Lee WS, Hediger MA, et al.: Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney. J Biol Chem 269: 17713–17722, 1994
Gamba G, Saltzberg SN, Lombardi M, Miyanoshita A, Lytton J, Hediger MA, et al.: Primary structure and functional expression of a cDNA encoding the thiazide-sensitive, electroneutral sodium-chloride cotransporter. Proc Natl Acad Sci U S A 90: 2749–2753, 1993
Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, et al.: Amiloride-sensitive epithelial Na + channel is made of three homologous subunits. Nature 367: 463–467, 1994
Zhu Q, Wang Z, Xia M, Li PL, Van Tassell BW, Abbate A, et al.: Silencing of hypoxia-inducible factor-1 α gene attenuated angiotensin II-induced renal injury in Sprague-Dawley rats. Hypertension 58: 657–664, 2011
Thomas JL, Pham H, Li Y, Hall E, Perkins GA, Ali SS, et al.: Hypoxia-inducible factor-1 α activation improves renal oxygenation and mitochondrial function in early chronic kidney disease. Am J Physiol Renal Physiol 313: F282–F290, 2017
Haase VH: Hypoxia-inducible factors in the kidney. Am J Physiol Renal Physiol 291: F271–F281, 2006
Zhu Q, Hu J, Han WQ, Zhang F, Li PL, Wang Z, et al.: Silencing of HIF prolyl-hydroxylase 2 gene in the renal medulla attenuates salt-sensitive hypertension in Dahl S rats. Am J Hypertens 27: 107–113, 2014
Brezis M, Agmon Y, Epstein FH: Determinants of intrarenal oxygenation. I. Effects of diuretics. Am J Physiol 267: F1059–F1062, 1994
Sassi A, Wang Y, Chassot A, Komarynets O, Roth I, Olivier V, et al.: Interaction between epithelial sodium channel γ-subunit and claudin-8 modulates paracellular sodium permeability in renal collecting duct. J Am Soc Nephrol 31: 1009–1023, 2020
Gruber M, Hu CJ, Johnson RS, Brown EJ, Keith B, Simon MC: Acute postnatal ablation of Hif-2 α results in anemia. Proc Natl Acad Sci U S A 104: 2301–2306, 2007
Perrier R, Boscardin E, Malsure S, Sergi C, Maillard MP, Loffing J, et al.: Severe salt-losing syndrome and hyperkalemia induced by adult nephron-specific knockout of the epithelial sodium channel α -subunit. J Am Soc Nephrol 27: 2309–2318, 2016
Bens M, Vallet V, Cluzeaud F, Pascual-Letallec L, Kahn A, Rafestin-Oblin ME, et al.: Corticosteroid-dependent sodium transport in a novel immortalized mouse collecting duct principal cell line. J Am Soc Nephrol 10: 923–934, 1999
Zufferey R, Nagy D, Mandel RJ, Naldini L, Trono D: Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat Biotechnol 15: 871–875, 1997
Schreiber A, Shulhevich Y, Geraci S, Hesser J, Stsepankou D, Neudecker S, et al.: Transcutaneous measurement of renal function in conscious mice. Am J Physiol Renal Physiol 303: F783–F788, 2012
Udwan K, Abed A, Roth I, Dizin E, Maillard M, Bettoni C, et al.: Dietary sodium induces a redistribution of the tubular metabolic workload. J Physiol 595: 6905–6922, 2017
Hasler U, Vinciguerra M, Vandewalle A, Martin P-Y, Féraille E: Dual effects of hypertonicity on aquaporin-2 expression in cultured renal collecting duct principal cells. J Am Soc Nephrol 16: 1571–1582, 2005
Wagner CA, Loffing-Cueni D, Yan Q, Schulz N, Fakitsas P, Carrel M, et al.: Mouse model of type II bartter's syndrome. II. Altered expression of renal sodium- AND water-transporting proteins. Am J Physiol Renal Physiol 294: F1373–F1380, 2008 18322017
Sorensen MV, Grossmann S, Roesinger M, Gresko N, Todkar AP, Barmettler G, et al.: Rapid dephosphorylation of the renal sodium chloride cotransporter in response to oral potassium intake in mice. Kidney Int 83: 811–824, 2013
Hasler U, Mordasini D, Bianchi M, Vandewalle A, Féraille E, Martin P-Y: Dual influence of aldosterone on AQP2 expression in cultured renal collecting duct principal cells. Journal of Biological Chemistry 278: 21639–21648, 2003
Carranza ML, Féraille E, Favre H: Protein kinase C-dependent phosphorylation of na(+)-K(+)-atpase alpha-subunit in rat kidney cortical tubules. Am J Physiol 271: C136–C143, 1996 8760039
Leroy V, De Seigneux S, Agassiz V, Hasler U, Rafestin-Oblin ME, Vinciguerra M, et al.: Aldosterone activates NF- κ B in the collecting duct. J Am Soc Nephrol 20: 131–144, 2009
O’Hagan KA, Cocchiglia S, Zhdanov AV, Tambuwala MM, Cummins EP, Monfared M, et al.: PGC-1alpha is coupled to HIF-1 α -dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells. Proc Natl Acad Sci U S A 106: 2188–2193, 2009
Colice G, Yen S, Ramirez G, Dietz J, Ou LC: Acute hypoxia-induced diuresis in rats. Aviat Space Environ Med 62: 551–554, 1991
Swenson ER, et al.: Diuretic effect of acute hypoxia in humans: relationship to hypoxic ventilatory responsiveness and renal hormones. J Appl Physiol 78: 377–383 1995
Bhalla V, Oyster NM, Fitch AC, Wijngaarden MA, Neumann D, Schlattner U, et al.: AMP-activated kinase inhibits the epithelial Na + channel through functional regulation of the ubiquitin ligase Nedd4-2. J Biol Chem 281: 26159–26169, 2006
Farsijani NM, Liu Q, Kobayashi H, Davidoff O, Sha F, Fandrey J, et al.: Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin. J Clin Invest 126: 1425–1437, 2016
Amasheh S, Milatz S, Krug SM, Bergs M, Amasheh M, Schulzke JD, et al.: Na + absorption defends from paracellular back-leakage by claudin-8 upregulation. Biochem Biophys Res Commun 378: 45–50, 2009
Penton D, Czogalla J, Wengi A, Himmerkus N, Loffing-Cueni D, Carrel M, et al.: Extracellular K + rapidly controls NaCl cotransporter phosphorylation in the native distal convoluted tubule by Cl − -dependent and independent mechanisms. J Physiol 594: 6319–6331, 2016
Kraus A, Peters DJM, Klanke B, Weidemann A, Willam C, Schley G, et al.: HIF-1 α promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease. Kidney Int 94: 887–899, 2018
Husted RF, Lu H, Sigmund RD, Stokes JB: Oxygen regulation of the epithelial Na channel in the collecting duct. Am J Physiol Renal Physiol 300: F412–F424, 2011
Doughan AK, Harrison DG, Dikalov SI: Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res 102: 488–496, 2008
Miyata K, Rahman M, Shokoji T, Nagai Y, Zhang GX, Sun GP, et al.: Aldosterone stimulates reactive oxygen species production through activation of NADPH oxidase in rat mesangial cells. J Am Soc Nephrol 16: 2906–2912, 2005
Kitiyakara C, Chabrashvili T, Chen Y, Blau J, Karber A, Aslam S, et al.: Salt intake, oxidative stress, and renal expression of NADPH oxidase and superoxide dismutase. J Am Soc Nephrol 14: 2775–2782, 2003