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Research Article

KLHL3 Knockout Mice Reveal the Physiological Role of KLHL3 and the Pathophysiology of Pseudohypoaldosteronism Type II Caused by Mutant KLHL3

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Article: e00508-16 | Received 25 Sep 2016, Accepted 29 Dec 2016, Published online: 17 Mar 2023

REFERENCES

  • Gordon RD. 1986. Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate. Hypertension 8:93–102. https://doi.org/10.1161/01.HYP.8.2.93.
  • Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP. 2001. Human hypertension caused by mutations in WNK kinases. Science 293:1107–1112. https://doi.org/10.1126/science.1062844.
  • Sohara E, Uchida S. 2016. Kelch-like 3/Cullin 3 ubiquitin ligase complex and WNK signaling in salt-sensitive hypertension and electrolyte disorder. Nephrol Dial Transplant 31:1417–1424. https://doi.org/10.1093/ndt/gfv259.
  • Hossain Khan MZ, Sohara E, Ohta A, Chiga M, Inoue Y, Isobe K, Wakabayashi M, Oi K, Rai T, Sasaki S, Uchida S. 2012. Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates its ubiquitination. Biochem Biophys Res Commun 425:456–461. https://doi.org/10.1016/j.bbrc.2012.07.124.
  • Moriguchi T, Urushiyama S, Hisamoto N, Iemura S, Uchida S, Natsume T, Matsumoto K, Shibuya H. 2005. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. J Biol Chem 280:42685–42693. https://doi.org/10.1074/jbc.M510042200.
  • Vitari AC, Deak M, Morrice NA, Alessi DR. 2005. The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases. Biochem J 391:17–24. https://doi.org/10.1042/BJ20051180.
  • Chiga M, Rafiqi FH, Alessi DR, Sohara E, Ohta A, Rai T, Sasaki S, Uchida S. 2011. Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade. J Cell Sci 124:1391–1395. https://doi.org/10.1242/jcs.084111.
  • Yang SS, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, Uchida K, Lin SH, Moriguchi T, Shibuya H, Kondo Y, Sasaki S, Uchida S. 2007. Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model. Cell Metab 5:331–344. https://doi.org/10.1016/j.cmet.2007.03.009.
  • Bergaya S, Faure S, Baudrie V, Rio M, Escoubet B, Bonnin P, Henrion D, Loirand G, Achard JM, Jeunemaitre X, Hadchouel J. 2011. WNK1 regulates vasoconstriction and blood pressure response to α1-adrenergic stimulation in mice. Hypertension 58:439–445. https://doi.org/10.1161/HYPERTENSIONAHA.111.172429.
  • Vidal-Petiot E, Elvira-Matelot E, Mutig K, Soukaseum C, Baudrie V, Wu S, Cheval L, Huc E, Cambillau M, Bachmann S, Doucet A, Jeunemaitre X, Hadchouel J. 2013. WNK1-related familial hyperkalemic hypertension results from an increased expression of L-WNK1 specifically in the distal nephron. Proc Natl Acad Sci U S A 110:14366–14371. https://doi.org/10.1073/pnas.1304230110.
  • Castaneda-Bueno M, Cervantes-Perez LG, Vazquez N, Uribe N, Kantesaria S, Morla L, Bobadilla NA, Doucet A, Alessi DR, Gamba G. 2012. Activation of the renal Na+:Cl− cotransporter by angiotensin II is a WNK4-dependent process. Proc Natl Acad Sci U S A 109:7929–7934. https://doi.org/10.1073/pnas.1200947109.
  • Rafiqi FH, Zuber AM, Glover M, Richardson C, Fleming S, Jovanovic S, Jovanovic A, O'Shaughnessy KM, Alessi DR. 2010. Role of the WNK-activated SPAK kinase in regulating blood pressure. EMBO Mol Med 2:63–75. https://doi.org/10.1002/emmm.200900058.
  • Yang SS, Lo YF, Wu CC, Lin SW, Yeh CJ, Chu P, Sytwu HK, Uchida S, Sasaki S, Lin SH. 2010. SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction. J Am Soc Nephrol 21:1868–1877. https://doi.org/10.1681/ASN.2009121295.
  • Takahashi D, Mori T, Nomura N, Khan MZ, Araki Y, Zeniya M, Sohara E, Rai T, Sasaki S, Uchida S. 2014. WNK4 is the major WNK positively regulating NCC in the mouse kidney. Biosci Rep 34:e00107. https://doi.org/10.1042/BSR20140047.
  • Richardson C, Alessi DR. 2008. The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signaling pathway. J Cell Sci 121:3293–3304. https://doi.org/10.1242/jcs.029223.
  • Uchida S, Sohara E, Rai T, Sasaki S. 2014. Regulation of with-no-lysine kinase signaling by Kelch-like proteins. Biol Cell 106:45–56. https://doi.org/10.1111/boc.201300069.
  • Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, Tikhonova IR, Bjornson R, Mane SM, Colussi G, Lebel M, Gordon RD, Semmekrot BA, Poujol A, Valimaki MJ, De Ferrari ME, Sanjad SA, Gutkin M, Karet FE, Tucci JR, Stockigt JR, Keppler-Noreuil KM, Porter CC, Anand SK, Whiteford ML, Davis ID, Dewar SB, Bettinelli A, Fadrowski JJ, Belsha CW, Hunley TE, Nelson RD, Trachtman H, Cole TR, Pinsk M, Bockenhauer D, Shenoy M, Vaidyanathan P, Foreman JW, Rasoulpour M, Thameem F, Al-Shahrouri HZ, Radhakrishnan J, Gharavi AG, Goilav B, Lifton RP. 2012. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482:98–102. https://doi.org/10.1038/nature10814.
  • Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N, Pylypenko O, Beaurain G, Bonnefond A, Sand O, Simian C, Vidal-Petiot E, Soukaseum C, Mandet C, Broux F, Chabre O, Delahousse M, Esnault V, Fiquet B, Houillier P, Bagnis CI, Koenig J, Konrad M, Landais P, Mourani C, Niaudet P, Probst V, Thauvin C, Unwin RJ, Soroka SD, Ehret G, Ossowski S, Caulfield M, Bruneval P, Estivill X, Froguel P, Hadchouel J, Schott JJ, Jeunemaitre X. 2012. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat Genet 44:456–460. https://doi.org/10.1038/ng.2218.
  • Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, Chiga M, Kikuchi E, Nomura N, Mori Y, Matsuo H, Murata T, Nomura S, Asano T, Kawaguchi H, Nonoyama S, Rai T, Sasaki S, Uchida S. 2013. Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension. Cell Rep 3:858–868. https://doi.org/10.1016/j.celrep.2013.02.024.
  • Wu G, Peng JB. 2013. Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation. FEBS Lett 587:1717–1722. https://doi.org/10.1016/j.febslet.2013.04.032.
  • Shibata S, Zhang J, Puthumana J, Stone KL, Lifton RP. 2013. Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4. Proc Natl Acad Sci U S A 110:7838–7843. https://doi.org/10.1073/pnas.1304592110.
  • Ohta A, Schumacher FR, Mehellou Y, Johnson C, Knebel A, Macartney TJ, Wood NT, Alessi DR, Kurz T. 2013. The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. Biochem J 451:111–122. https://doi.org/10.1042/BJ20121903.
  • Susa K, Sohara E, Rai T, Zeniya M, Mori Y, Mori T, Chiga M, Nomura N, Nishida H, Takahashi D, Isobe K, Inoue Y, Takeishi K, Takeda N, Sasaki S, Uchida S. 2014. Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice. Hum Mol Genet 23:5052–5060. https://doi.org/10.1093/hmg/ddu217.
  • Yoshizaki Y, Mori Y, Tsuzaki Y, Mori T, Nomura N, Wakabayashi M, Takahashi D, Zeniya M, Kikuchi E, Araki Y, Ando F, Isobe K, Nishida H, Ohta A, Susa K, Inoue Y, Chiga M, Rai T, Sasaki S, Uchida S, Sohara E. 2015. Impaired degradation of WNK by Akt and PKA phosphorylation of KLHL3. Biochem Biophys Res Commun 467:229–234. https://doi.org/10.1016/j.bbrc.2015.09.184.
  • Shibata S, Arroyo JP, Castaneda-Bueno M, Puthumana J, Zhang J, Uchida S, Stone KL, Lam TT, Lifton RP. 2014. Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation. Proc Natl Acad Sci U S A 111:15556–15561. https://doi.org/10.1073/pnas.1418342111.
  • Zeniya M, Sohara E, Kita S, Iwamoto T, Susa K, Mori T, Oi K, Chiga M, Takahashi D, Yang SS, Lin SH, Rai T, Sasaki S, Uchida S. 2013. Dietary salt intake regulates WNK3-SPAK-NKCC1 phosphorylation cascade in mouse aorta through angiotensin II. Hypertension 62:872–878. https://doi.org/10.1161/HYPERTENSIONAHA.113.01543.
  • Susa K, Kita S, Iwamoto T, Yang SS, Lin SH, Ohta A, Sohara E, Rai T, Sasaki S, Alessi DR, Uchida S. 2012. Effect of heterozygous deletion of WNK1 on the WNK-OSR1/ SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels. Clin Exp Nephrol 16:530–538. https://doi.org/10.1007/s10157-012-0590-x.
  • Yang L, Cai X, Zhou J, Chen S, Chen Y, Chen Z, Wang Q, Fang Z, Zhou L. 2013. STE20/SPS1-related proline/alanine-rich kinase is involved in plasticity of GABA signaling function in a mouse model of acquired epilepsy. PLoS One 8:e74614. https://doi.org/10.1371/journal.pone.0074614.
  • Alessi DR, Zhang J, Khanna A, Hochdorfer T, Shang Y, Kahle KT. 2014. The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters. Sci Signal 7:re3. https://doi.org/10.1126/scisignal.2005365.
  • Kahle KT, Khanna AR, Alper SL, Adragna NC, Lauf PK, Sun D, Delpire E. 2015. K-Cl cotransporters, cell volume homeostasis, and neurological disease. Trends Mol Med 21:513–523. https://doi.org/10.1016/j.molmed.2015.05.008.
  • Moniz S, Matos P, Jordan P. 2008. WNK2 modulates MEK1 activity through the Rho GTPase pathway. Cell Signal 20:1762–1768. https://doi.org/10.1016/j.cellsig.2008.06.002.
  • Xu BE, Stippec S, Lenertz L, Lee BH, Zhang W, Lee YK, Cobb MH. 2004. WNK1 activates ERK5 by an MEKK2/3-dependent mechanism. J Biol Chem 279:7826–7831. https://doi.org/10.1074/jbc.M313465200.
  • Lee BH, Chen W, Stippec S, Cobb MH. 2007. Biological cross-talk between WNK1 and the transforming growth factor beta-Smad signaling pathway. J Biol Chem 282:17985–17996. https://doi.org/10.1074/jbc.M702664200.
  • DasGupta R, Kaykas A, Moon RT, Perrimon N. 2005. Functional genomic analysis of the Wnt-wingless signaling pathway. Science 308:826–833. https://doi.org/10.1126/science.1109374.
  • Lalioti MD, Zhang J, Volkman HM, Kahle KT, Hoffmann KE, Toka HR, Nelson-Williams C, Ellison DH, Flavell R, Booth CJ, Lu Y, Geller DS, Lifton RP. 2006. Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule. Nat Genet 38:1124–1132. https://doi.org/10.1038/ng1877.
  • Veitia RA. 2007. Exploring the molecular etiology of dominant-negative mutations. Plant Cell 19:3843–3851. https://doi.org/10.1105/tpc.107.055053.
  • Ogura T, Tong KI, Mio K, Maruyama Y, Kurokawa H, Sato C, Yamamoto M. 2010. Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains. Proc Natl Acad Sci U S A 107:2842–2847. https://doi.org/10.1073/pnas.0914036107.
  • Zeniya M, Morimoto N, Takahashi D, Mori Y, Mori T, Ando F, Araki Y, Yoshizaki Y, Inoue Y, Isobe K, Nomura N, Oi K, Nishida H, Sasaki S, Sohara E, Rai T, Uchida S. 2015. Kelch-like protein 2 mediates angiotensin II-with no lysine 3 signaling in the regulation of vascular tonus. J Am Soc Nephrol 26:2129–2138. https://doi.org/10.1681/ASN.2014070639.
  • Khanna A, Walcott BP, Kahle KT. 2013. Limitations of current GABA agonists in neonatal seizures: toward GABA modulation via the targeting of neuronal Cl− transport. Front Neurol 4:78. https://doi.org/10.3389/fneur.2013.00078.
  • Rinehart J, Vazquez N, Kahle KT, Hodson CA, Ring AM, Gulcicek EE, Louvi A, Bobadilla NA, Gamba G, Lifton RP. 2011. WNK2 kinase is a novel regulator of essential neuronal cation-chloride cotransporters. J Biol Chem 286:30171–30180. https://doi.org/10.1074/jbc.M111.222893.
  • Zhao H, Nepomuceno R, Gao X, Foley LM, Wang S, Begum G, Zhu W, Pigott VM, Falgoust LM, Kahle KT, Yang SS, Lin SH, Alper SL, Hitchens TK, Hu S, Zhang Z, Sun D. 9February2016. Deletion of the WNK3-SPAK kinase complex in mice improves radiographic and clinical outcomes in malignant cerebral edema after ischemic stroke. J Cereb Blood Flow Metab. Epub ahead of print.
  • Shekarabi M, Girard N, Riviere JB, Dion P, Houle M, Toulouse A, Lafreniere RG, Vercauteren F, Hince P, Laganiere J, Rochefort D, Faivre L, Samuels M, Rouleau GA. 2008. Mutations in the nervous system: specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II. J Clin Invest 118:2496–2505. https://doi.org/10.1172/JCI34088.
  • Zhang Y, Viennois E, Xiao B, Baker MT, Yang S, Okoro I, Yan Y. 2013. Knockout of Ste20-like proline/alanine-rich kinase (SPAK) attenuates intestinal inflammation in mice. Am J Pathol 182:1617–1628. https://doi.org/10.1016/j.ajpath.2013.01.028.
  • Xie J, Yoon J, Yang SS, Lin SH, Huang CL. 2013. WNK1 protein kinase regulates embryonic cardiovascular development through the OSR1 signaling cascade. J Biol Chem 288:8566–8574. https://doi.org/10.1074/jbc.M113.451575.
  • Zhang C, Meermeier NP, Terker AS, Blankenstein KI, Singer JD, Hadchouel J, Ellison DH, Yang CL. 2016. Degradation by Cullin 3 and effect on WNK kinases suggest a role of KLHL2 in the pathogenesis of familial hyperkalemic hypertension. Biochem Biophys Res Commun 469:44–48. https://doi.org/10.1016/j.bbrc.2015.11.067.
  • Takahashi D, Mori T, Wakabayashi M, Mori Y, Susa K, Zeniya M, Sohara E, Rai T, Sasaki S, Uchida S. 2013. KLHL2 interacts with and ubiquitinates WNK kinases. Biochem Biophys Res Commun 437:457–462. https://doi.org/10.1016/j.bbrc.2013.06.104.
  • Sibbe M, Kulik A. 6September2016. GABAergic regulation of adult hippocampal neurogenesis. Mol Neurobiol. Epub ahead of print.
  • Begum G, Yuan H, Kahle KT, Li L, Wang S, Shi Y, Shmukler BE, Yang SS, Lin SH, Alper SL, Sun D. 2015. Inhibition of WNK3 kinase signaling reduces brain damage and accelerates neurological recovery after stroke. Stroke 46:1956–1965. https://doi.org/10.1161/STROKEAHA.115.008939.
  • Mori Y, Mori T, Wakabayashi M, Yoshizaki Y, Zeniya M, Sohara E, Rai T, Uchida S. 2015. Involvement of selective autophagy mediated by p62/SQSTM1 in KLHL3-dependent WNK4 degradation. Biochem J 472:33–41. https://doi.org/10.1042/BJ20150500.
  • Kigoshi Y, Tsuruta F, Chiba T. 2011. Ubiquitin ligase activity of Cul3-KLHL7 protein is attenuated by autosomal dominant retinitis pigmentosa causative mutation. J Biol Chem 286:33613–33621. https://doi.org/10.1074/jbc.M111.245126.
  • Suzuki T, Maher J, Yamamoto M. 2011. Select heterozygous Keap1 mutations have a dominant-negative effect on wild-type Keap1 in vivo. Cancer Res 71:1700–1709. https://doi.org/10.1158/0008-5472.CAN-10-2939.
  • Ji AX, Prive GG. 2013. Crystal structure of KLHL3 in complex with Cullin3. PLoS One 8:e60445. https://doi.org/10.1371/journal.pone.0060445.
  • Mori Y, Wakabayashi M, Mori T, Araki Y, Sohara E, Rai T, Sasaki S, Uchida S. 2013. Decrease of WNK4 ubiquitination by disease-causing mutations of KLHL3 through different molecular mechanisms. Biochem Biophys Res Commun 439:30–34. https://doi.org/10.1016/j.bbrc.2013.08.035.
  • Sohara E, Rai T, Yang SS, Uchida K, Nitta K, Horita S, Ohno M, Harada A, Sasaki S, Uchida S. 2006. Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation. Proc Natl Acad Sci U S A 103:14217–14222. https://doi.org/10.1073/pnas.0602331103.
  • Sakai K, Miyazaki J. 1997. A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission. Biochem Biophys Res Commun 237:318–324. https://doi.org/10.1006/bbrc.1997.7111.
  • Araki Y, Rai T, Sohara E, Mori T, Inoue Y, Isobe K, Kikuchi E, Ohta A, Sasaki S, Uchida S. 2015. Generation and analysis of knock-in mice carrying pseudohypoaldosteronism type II-causing mutations in the cullin 3 gene. Biol Open 4:1509–1517. https://doi.org/10.1242/bio.013276.
  • Oi K, Sohara E, Rai T, Misawa M, Chiga M, Alessi DR, Sasaki S, Uchida S. 2012. A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC cotransporters in vivo. Biol Open 1:120–127. https://doi.org/10.1242/bio.2011048.
  • Sohara E, Rai T, Yang SS, Ohta A, Naito S, Chiga M, Nomura N, Lin SH, Vandewalle A, Ohta E, Sasaki S, Uchida S. 2011. Acute insulin stimulation induces phosphorylation of the Na-Cl cotransporter in cultured distal mpkDCT cells and mouse kidney. PLoS One 6:e24277. https://doi.org/10.1371/journal.pone.0024277.
  • Nishida H, Sohara E, Nomura N, Chiga M, Alessi DR, Rai T, Sasaki S, Uchida S. 2012. Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice. Hypertension 60:981–990. https://doi.org/10.1161/HYPERTENSIONAHA.112.201509.
  • Isobe K, Mori T, Asano T, Kawaguchi H, Nonoyama S, Kumagai N, Kamada F, Morimoto T, Hayashi M, Sohara E, Rai T, Sasaki S, Uchida S. 2013. Development of enzyme-linked immunosorbent assays for urinary thiazide-sensitive Na-Cl cotransporter measurement. Am J Physiol Renal Physiol 305:F1374–F1381. https://doi.org/10.1152/ajprenal.00208.2013.
  • Kikuchi E, Mori T, Zeniya M, Isobe K, Ishigami-Yuasa M, Fujii S, Kagechika H, Ishihara T, Mizushima T, Sasaki S, Sohara E, Rai T, Uchida S. 2015. Discovery of novel SPAK inhibitors that block WNK kinase signaling to cation chloride transporters. J Am Soc Nephrol 26:1525–1536. https://doi.org/10.1681/ASN.2014060560.
  • Ohno M, Uchida K, Ohashi T, Nitta K, Ohta A, Chiga M, Sasaki S, Uchida S. 2011. Immunolocalization of WNK4 in mouse kidney. Histochem Cell Biol 136:25–35. https://doi.org/10.1007/s00418-011-0827-x.

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