1932

Abstract

The kidney maintains electrolyte, water, and acid-base balance, eliminates foreign and waste compounds, regulates blood pressure, and secretes hormones. There are at least 16 different highly specialized epithelial cell types in the mammalian kidney. The number of specialized endothelial cells, immune cells, and interstitial cell types might even be larger. The concerted interplay between different cell types is critical for kidney function. Traditionally, cells were defined by their function or microscopical morphological appearance. With the advent of new single-cell modalities such as transcriptomics, epigenetics, metabolomics, and proteomics we are entering into a new era of cell type definition. This new technological revolution provides new opportunities to classify cells in the kidney and understand their functions.

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2022-02-10
2024-06-25
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Literature Cited

  1. 1. 
    Bernard C. 1878. Leçons sur les phénomènes de la vie communs aux animaux et aux végétaux Paris: J.B. Baillière
    [Google Scholar]
  2. 2. 
    Smith HW. 1953. From Fish to Philosopher Boston: Little, Brown
    [Google Scholar]
  3. 3. 
    Smith HW. 1956. Principles of Renal Physiology New York: Oxford Univ. Press
    [Google Scholar]
  4. 4. 
    Smith HW. 1959. The fate of sodium and water in the renal tubules. Bull. N. Y. Acad. Med. 35:293–316
    [Google Scholar]
  5. 5. 
    Hoenig MP, Zeidel ML. 2014. Homeostasis, the milieu intérieur, and the wisdom of the nephron. Clin. J. Am. Soc. Nephrol. 9:1272–81
    [Google Scholar]
  6. 6. 
    Gong R. 2008. The renal circulations and glomerular ultrafiltration. Brenner and Rector's The Kidney91–129 Philadelphia: WB Saunders. , 8th ed..
    [Google Scholar]
  7. 7. 
    Stein JH, Boonjarern S, Wilson CB, Ferris TF 1973. Alterations in intrarenal blood flow distribution. Methods of measurement and relationship to sodium balance. Circ. Res. 32:Suppl. 161–72
    [Google Scholar]
  8. 8. 
    Pagel H, Jelkmann W, Weiss C 1989. O2-supply to the kidneys and the production of erythropoietin. Respir. Physiol. 77:111–17
    [Google Scholar]
  9. 9. 
    Tisher C, Madsen K. 2008. Anatomy of the kidney. Brenner and Rector's The Kidney25–90 Philadelphia: WB Saunders. , 8th ed..
    [Google Scholar]
  10. 10. 
    Stolz DB, Sims-Lucas S. 2015. Unwrapping the origins and roles of the renal endothelium. Pediatr. Nephrol. 30:865–72
    [Google Scholar]
  11. 11. 
    Park J, Shrestha R, Qiu C, Kondo A, Huang S et al. 2018. Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360:758–63
    [Google Scholar]
  12. 12. 
    Molema G, Aird WC. 2012. Vascular heterogeneity in the kidney. Semin. Nephrol. 32:145–55
    [Google Scholar]
  13. 13. 
    Barry DM, McMillan EA, Kunar B, Lis R, Zhang T et al. 2019. Molecular determinants of nephron vascular specialization in the kidney. Nat. Commun. 10:5705
    [Google Scholar]
  14. 14. 
    Dumas SJ, Meta E, Borri M, Goveia J, Rohlenova K et al. 2020. Single-cell RNA sequencing reveals renal endothelium heterogeneity and metabolic adaptation to water deprivation. J. Am. Soc. Nephrol. 31:118–38
    [Google Scholar]
  15. 15. 
    Tanabe K, Wada J, Sato Y. 2020. Targeting angiogenesis and lymphangiogenesis in kidney disease. Nat. Rev. Nephrol. 16:289–303
    [Google Scholar]
  16. 16. 
    Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M et al. 2008. VEGF inhibition and renal thrombotic microangiopathy. N. Engl. J. Med. 358:1129–36
    [Google Scholar]
  17. 17. 
    Eremina V, Sood M, Haigh J, Nagy A, Lajoie G et al. 2003. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J. Clin. Investig. 111:707–16
    [Google Scholar]
  18. 18. 
    Dhillon P, Park J, Hurtado Del Pozo C, Li L, Doke T et al. 2021. The nuclear receptor ESRRA protects from kidney disease by coupling metabolism and differentiation. Cell Metab 33:379–94.e8
    [Google Scholar]
  19. 19. 
    Miao Z, Balzer MS, Ma Z, Liu H, Wu J et al. 2021. Single cell regulatory landscape of the mouse kidney highlights cellular differentiation programs and disease targets. Nat. Commun. 12:2277
    [Google Scholar]
  20. 20. 
    Chung JJ, Goldstein L, Chen YJ, Lee J, Webster JD et al. 2020. Single-cell transcriptome profiling of the kidney glomerulus identifies key cell types and reactions to injury. J. Am. Soc. Nephrol. 31:2341–54
    [Google Scholar]
  21. 21. 
    Pollak MR, Quaggin SE, Hoenig MP, Dworkin LD. 2014. The glomerulus: the sphere of influence. Clin. J. Am. Soc. Nephrol. 9:1461–69
    [Google Scholar]
  22. 22. 
    Grigorieva IV, Oszwald A, Grigorieva EF, Schachner H, Neudert B et al. 2019. A novel role for GATA3 in mesangial cells in glomerular development and injury. J. Am. Soc. Nephrol. 30:1641–58
    [Google Scholar]
  23. 23. 
    Marciano DK. 2019. Mesangial cells: the tuft guys of glomerular development. J. Am. Soc. Nephrol. 30:1551–53
    [Google Scholar]
  24. 24. 
    Huber TB, Benzing T. 2005. The slit diaphragm: a signaling platform to regulate podocyte function. Curr. Opin. Nephrol. Hypertens. 14:211–16
    [Google Scholar]
  25. 25. 
    Faul C, Asanuma K, Yanagida-Asanuma E, Kim K, Mundel P 2007. Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 17:428–37
    [Google Scholar]
  26. 26. 
    Boute N, Gribouval O, Roselli S, Benessy F, Lee H et al. 2000. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat. Genet. 24:349–54
    [Google Scholar]
  27. 27. 
    Tryggvason K, Patrakka J, Wartiovaara J. 2006. Hereditary proteinuria syndromes and mechanisms of proteinuria. N. Engl. J. Med. 354:1387–401
    [Google Scholar]
  28. 28. 
    Kestilä M, Lenkkeri U, Männikkö M, Lamerdin J, McCready P et al. 1998. Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome. Mol. Cell 1:575–82
    [Google Scholar]
  29. 29. 
    Curthoys NP, Moe OW. 2014. Proximal tubule function and response to acidosis. Clin. J. Am. Soc. Nephrol. 9:1627–38
    [Google Scholar]
  30. 30. 
    Lopez-Nieto CE, You G, Bush KT, Barros EJ, Beier DR, Nigam SK. 1997. Molecular cloning and characterization of NKT, a gene product related to the organic cation transporter family that is almost exclusively expressed in the kidney. J. Biol. Chem. 272:6471–78
    [Google Scholar]
  31. 31. 
    Preisig PA, Rector FC Jr. 1988. Role of Na+-H+ antiport in rat proximal tubule NaCl absorption. Am. J. Physiol. 255:F461–65
    [Google Scholar]
  32. 32. 
    Moe OW, Preisig PA, Alpern RJ. 1990. Cellular model of proximal tubule NaCl and NaHCO3 absorption. Kidney Int. 38:605–11
    [Google Scholar]
  33. 33. 
    Aronson PS. 2002. Ion exchangers mediating NaCl transport in the renal proximal tubule. Cell Biochem. Biophys. 36:147–53
    [Google Scholar]
  34. 34. 
    Vallon V, Platt KA, Cunard R, Schroth J, Whaley J et al. 2011. SGLT2 mediates glucose reabsorption in the early proximal tubule. J. Am. Soc. Nephrol. 22:104–12
    [Google Scholar]
  35. 35. 
    Hummel CS, Lu C, Loo DD, Hirayama BA, Voss AA, Wright EM. 2011. Glucose transport by human renal Na+/d-glucose cotransporters SGLT1 and SGLT2. Am. J. Physiol. Cell Physiol. 300:C14–21
    [Google Scholar]
  36. 36. 
    Verrey F, Singer D, Ramadan T, Vuille-dit-Bille RN, Mariotta L, Camargo SM. 2009. Kidney amino acid transport. Pflügers Arch. 458:53–60
    [Google Scholar]
  37. 37. 
    McGivan JD, Bungard CI. 2007. The transport of glutamine into mammalian cells. Front. Biosci. 12:874–82
    [Google Scholar]
  38. 38. 
    Vallon V, Rose M, Gerasimova M, Satriano J, Platt KA et al. 2013. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am. J. Physiol. Ren. Physiol. 304:F156–67
    [Google Scholar]
  39. 39. 
    Bakris GL, Fonseca VA, Sharma K, Wright EM. 2009. Renal sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Kidney Int. 75:1272–77
    [Google Scholar]
  40. 40. 
    Torrents D, Estévez R, Pineda M, Fernández E, Lloberas J et al. 1998. Identification and characterization of a membrane protein (y+L amino acid transporter-1) that associates with 4F2hc to encode the amino acid transport activity y+L. A candidate gene for lysinuric protein intolerance. J. Biol. Chem. 273:32437–45
    [Google Scholar]
  41. 41. 
    Rossier G, Meier C, Bauch C, Summa V, Sordat B et al. 1999. LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine. J. Biol. Chem. 274:34948–54
    [Google Scholar]
  42. 42. 
    Romeo E, Dave MH, Bacic D, Ristic Z, Camargo SM et al. 2006. Luminal kidney and intestine SLC6 amino acid transporters of B0AT-cluster and their tissue distribution in Mus musculus. Am. J. Physiol. Ren. Physiol. 290:F376–83
    [Google Scholar]
  43. 43. 
    Seow HF, Bröer S, Bröer A, Bailey CG, Potter SJ et al. 2004. Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. Nat. Genet. 36:1003–7
    [Google Scholar]
  44. 44. 
    Kleta R, Romeo E, Ristic Z, Ohura T, Stuart C et al. 2004. Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder. Nat. Genet. 36:999–1002
    [Google Scholar]
  45. 45. 
    Shayakul C, Kanai Y, Lee WS, Brown D, Rothstein JD, Hediger MA. 1997. Localization of the high-affinity glutamate transporter EAAC1 in rat kidney. Am. J. Physiol. Ren. Physiol. 273:F1023–29
    [Google Scholar]
  46. 46. 
    Nigam SK. 2018. The SLC22 transporter family: a paradigm for the impact of drug transporters on metabolic pathways, signaling, and disease. Annu. Rev. Pharmacol. Toxicol. 58:663–87
    [Google Scholar]
  47. 47. 
    Nigam SK. 2015. What do drug transporters really do?. Nat. Rev. Drug Discov. 14:29–44
    [Google Scholar]
  48. 48. 
    Curthoys NP, Gstraunthaler G. 2001. Mechanism of increased renal gene expression during metabolic acidosis. Am. J. Physiol. Ren. Physiol. 281:F381–90
    [Google Scholar]
  49. 49. 
    Boron WF. 2006. Acid-base transport by the renal proximal tubule. J. Am. Soc. Nephrol. 17:2368–82
    [Google Scholar]
  50. 50. 
    Moret C, Dave MH, Schulz N, Jiang JX, Verrey F, Wagner CA. 2007. Regulation of renal amino acid transporters during metabolic acidosis. Am. J. Physiol. Ren. Physiol. 292:F555–66
    [Google Scholar]
  51. 51. 
    Christensen HN. 1990. Role of amino acid transport and countertransport in nutrition and metabolism. Physiol. Rev. 70:43–77
    [Google Scholar]
  52. 52. 
    Chaudhry FA, Reimer RJ, Edwards RH. 2002. The glutamine commute: take the N line and transfer to the A. J. Cell Biol. 157:349–55
    [Google Scholar]
  53. 53. 
    Moe OW. 2006. Kidney stones: pathophysiology and medical management. Lancet 367:333–44
    [Google Scholar]
  54. 54. 
    Moe OW, Preisig PA. 2006. Dual role of citrate in mammalian urine. Curr. Opin. Nephrol. Hypertens. 15:419–24
    [Google Scholar]
  55. 55. 
    Curthoys NP, Lowry OH. 1973. The distribution of glutaminase isoenzymes in the various structures of the nephron in normal, acidotic, and alkalotic rat kidney. J. Biol. Chem. 248:162–68
    [Google Scholar]
  56. 56. 
    Wright PA, Knepper MA. 1990. Phosphate-dependent glutaminase activity in rat renal cortical and medullary tubule segments. Am. J. Physiol. Ren. Physiol. 259:F961–70
    [Google Scholar]
  57. 57. 
    Wright PA, Knepper MA. 1990. Glutamate dehydrogenase activities in microdissected rat nephron segments: effects of acid-base loading. Am. J. Physiol. Ren. Physiol. 259:F53–59
    [Google Scholar]
  58. 58. 
    Molinas SM, Trumper L, Marinelli RA. 2012. Mitochondrial aquaporin-8 in renal proximal tubule cells: evidence for a role in the response to metabolic acidosis. Am. J. Physiol. Ren. Physiol. 303:F458–66
    [Google Scholar]
  59. 59. 
    Preisig PA, Alpern RJ. 1988. Chronic metabolic acidosis causes an adaptation in the apical membrane Na/H antiporter and basolateral membrane Na(HCO3)3 symporter in the rat proximal convoluted tubule. J. Clin. Investig. 82:1445–53
    [Google Scholar]
  60. 60. 
    Ambühl PM, Amemiya M, Danczkay M, Lötscher M, Kaissling B et al. 1996. Chronic metabolic acidosis increases NHE3 protein abundance in rat kidney. Am. J. Physiol. Ren. Physiol. 271:F917–25
    [Google Scholar]
  61. 61. 
    Wu MS, Biemesderfer D, Giebisch G, Aronson PS 1996. Role of NHE3 in mediating renal brush border Na+-H+ exchange. Adaptation to metabolic acidosis. J. Biol. Chem. 271:32749–52
    [Google Scholar]
  62. 62. 
    Solbu TT, Boulland JL, Zahid W, Lyamouri Bredahl MK, Amiry-Moghaddam M et al. 2005. Induction and targeting of the glutamine transporter SN1 to the basolateral membranes of cortical kidney tubule cells during chronic metabolic acidosis suggest a role in pH regulation. J. Am. Soc. Nephrol. 16:869–77
    [Google Scholar]
  63. 63. 
    Horie S, Moe O, Tejedor A, Alpern RJ 1990. Preincubation in acid medium increases Na/H antiporter activity in cultured renal proximal tubule cells. PNAS 87:4742–45
    [Google Scholar]
  64. 64. 
    Tannen RL, Ross BD. 1979. Ammoniagenesis by the isolated perfused rat kidney: the critical role of urinary acidification. Clin. Sci. 56:353–64
    [Google Scholar]
  65. 65. 
    Pajor AM. 1995. Sequence and functional characterization of a renal sodium/dicarboxylate cotransporter. J. Biol. Chem. 270:5779–85
    [Google Scholar]
  66. 66. 
    Qiu C, Huang S, Park J, Park Y, Ko YA et al. 2018. Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease. Nat. Med. 24:1721–31
    [Google Scholar]
  67. 67. 
    Kirita Y, Wu H, Uchimura K, Wilson PC, Humphreys BD 2020. Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury. PNAS 117:15874–83
    [Google Scholar]
  68. 68. 
    de Lau W, Barker N, Low TY, Koo BK, Li VS et al. 2011. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476:293–97
    [Google Scholar]
  69. 69. 
    Walker JV, Zhuang H, Singer D, Illsley CS, Kok WL et al. 2019. Transit amplifying cells coordinate mouse incisor mesenchymal stem cell activation. Nat. Commun. 10:3596
    [Google Scholar]
  70. 70. 
    Rudman-Melnick V, Adam M, Potter A, Chokshi SM, Ma Q et al. 2020. Single-cell profiling of AKI in a murine model reveals novel transcriptional signatures, profibrotic phenotype, and epithelial-to-stromal crosstalk. J. Am. Soc. Nephrol. 31:2793–814
    [Google Scholar]
  71. 71. 
    Conway BR, O'Sullivan ED, Cairns C, O'Sullivan J, Simpson DJ et al. 2020. Kidney single-cell atlas reveals myeloid heterogeneity in progression and regression of kidney disease. J. Am. Soc. Nephrol. 31:2833–54
    [Google Scholar]
  72. 72. 
    Janosevic D, Myslinski J, McCarthy TW, Zollman A, Syed F et al. 2021. The orchestrated cellular and molecular responses of the kidney to endotoxin define a precise sepsis timeline. eLife 10:e62270
    [Google Scholar]
  73. 73. 
    Chen L, Clark JZ, Nelson JW, Kaissling B, Ellison DH, Knepper MA. 2019. Renal-tubule epithelial cell nomenclature for single-cell RNA-sequencing studies. J. Am. Soc. Nephrol. 30:1358–64
    [Google Scholar]
  74. 74. 
    Mount DB. 2014. Thick ascending limb of the loop of Henle. Clin. J. Am. Soc. Nephrol. 9:1974–86
    [Google Scholar]
  75. 75. 
    Nielsen S, Pallone T, Smith BL, Christensen EI, Agre P, Maunsbach AB 1995. Aquaporin-1 water channels in short and long loop descending thin limbs and in descending vasa recta in rat kidney. Am. J. Physiol. Ren. Physiol. 268:F1023–37
    [Google Scholar]
  76. 76. 
    Hebert SC, Mount DB, Gamba G. 2004. Molecular physiology of cation-coupled Cl cotransport: the SLC12 family. Pflügers Arch 447:580–93
    [Google Scholar]
  77. 77. 
    Burg M, Stoner L, Cardinal J, Green N 1973. Furosemide effect on isolated perfused tubules. Am. J. Physiol. 225:119–24
    [Google Scholar]
  78. 78. 
    Xu JZ, Hall AE, Peterson LN, Bienkowski MJ, Eessalu TE, Hebert SC. 1997. Localization of the ROMK protein on apical membranes of rat kidney nephron segments. Am. J. Physiol. Ren. Physiol. 273:F739–48
    [Google Scholar]
  79. 79. 
    Ho K, Nichols CG, Lederer WJ, Lytton J, Vassilev PM et al. 1993. Cloning and expression of an inwardly rectifying ATP-regulated potassium channel. Nature 362:31–38
    [Google Scholar]
  80. 80. 
    Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A et al. 1996. Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat. Genet. 14:152–56
    [Google Scholar]
  81. 81. 
    Konrad M, Schaller A, Seelow D, Pandey AV, Waldegger S et al. 2006. Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. Am. J. Hum. Genet. 79:949–57
    [Google Scholar]
  82. 82. 
    Lee JW, Chou CL, Knepper MA. 2015. Deep sequencing in microdissected renal tubules identifies nephron segment-specific transcriptomes. J. Am. Soc. Nephrol. 26:2669–77
    [Google Scholar]
  83. 83. 
    Gorski M, Tin A, Garnaas M, McMahon GM, Chu AY et al. 2015. Genome-wide association study of kidney function decline in individuals of European descent. Kidney Int 87:1017–29
    [Google Scholar]
  84. 84. 
    Böger CA, Gorski M, Li M, Hoffmann MM, Huang C et al. 2011. Association of eGFR-related loci identified by GWAS with incident CKD and ESRD. PLOS Genet. 7:e1002292
    [Google Scholar]
  85. 85. 
    Köttgen A, Glazer NL, Dehghan A, Hwang SJ, Katz R et al. 2009. Multiple loci associated with indices of renal function and chronic kidney disease. Nat. Genet. 41:712–17
    [Google Scholar]
  86. 86. 
    Olden M, Corre T, Hayward C, Toniolo D, Ulivi S et al. 2014. Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis. J. Am. Soc. Nephrol. 25:1869–82
    [Google Scholar]
  87. 87. 
    Cavallone D, Malagolini N, Serafini-Cessi F. 2001. Mechanism of release of urinary Tamm-Horsfall glycoprotein from the kidney GPI-anchored counterpart. Biochem. Biophys. Res. Commun. 280:110–14
    [Google Scholar]
  88. 88. 
    Padmanabhan S, Graham L, Ferreri NR, Graham D, McBride M, Dominiczak AF 2014. Uromodulin, an emerging novel pathway for blood pressure regulation and hypertension. Hypertension 64:918–23
    [Google Scholar]
  89. 89. 
    Rampoldi L, Scolari F, Amoroso A, Ghiggeri G, Devuyst O. 2011. The rediscovery of uromodulin (Tamm-Horsfall protein): from tubulointerstitial nephropathy to chronic kidney disease. Kidney Int. 80:338–47
    [Google Scholar]
  90. 90. 
    Scolari F, Izzi C, Ghiggeri GM. 2015. Uromodulin: from monogenic to multifactorial diseases. Nephrol. Dial. Transplant. 30:1250–56
    [Google Scholar]
  91. 91. 
    Vyletal P, Bleyer AJ, Kmoch S. 2010. Uromodulin biology and pathophysiology—an update. Kidney Blood Pressure Res 33:456–75
    [Google Scholar]
  92. 92. 
    Liu Y, Mo L, Goldfarb DS, Evan AP, Liang F et al. 2010. Progressive renal papillary calcification and ureteral stone formation in mice deficient for Tamm-Horsfall protein. Am. J. Physiol. Ren. Physiol. 299:F469–78
    [Google Scholar]
  93. 93. 
    Mo L, Liaw L, Evan AP, Sommer AJ, Lieske JC, Wu XR. 2007. Renal calcinosis and stone formation in mice lacking osteopontin, Tamm-Horsfall protein, or both. Am. J. Physiol. Ren. Physiol. 293:F1935–43
    [Google Scholar]
  94. 94. 
    Mo L, Huang HY, Zhu XH, Shapiro E, Hasty DL, Wu XR 2004. Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation. Kidney Int 66:1159–66
    [Google Scholar]
  95. 95. 
    Grant AM, Baker LR, Neuberger A. 1973. Urinary Tamm-Horsfall glycoprotein in certain kidney diseases and its content in renal and bladder calculi. Clin. Sci. 44:377–84
    [Google Scholar]
  96. 96. 
    Bates JM, Raffi HM, Prasadan K, Mascarenhas R, Laszik Z et al. 2004. Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int. 65:791–97
    [Google Scholar]
  97. 97. 
    Mo L, Zhu XH, Huang HY, Shapiro E, Hasty DL, Wu XR 2004. Ablation of the Tamm-Horsfall protein gene increases susceptibility of mice to bladder colonization by type 1-fimbriated Escherichia coli. Am. J. Physiol. Ren. Physiol. 286:F795–802
    [Google Scholar]
  98. 98. 
    Orskov I, Ferencz A, Orskov F 1980. Tamm-Horsfall protein or uromucoid is the normal urinary slime that traps type 1 fimbriated Escherichia coli. Lancet 1:887
    [Google Scholar]
  99. 99. 
    Graham LA, Padmanabhan S, Fraser NJ, Kumar S, Bates JM et al. 2014. Validation of uromodulin as a candidate gene for human essential hypertension. Hypertension 63:551–58
    [Google Scholar]
  100. 100. 
    Trudu M, Janas S, Lanzani C, Debaix H, Schaeffer C et al. 2013. Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. Nat. Med. 19:1655–60
    [Google Scholar]
  101. 101. 
    Nielsen S, Maunsbach AB, Ecelbarger CA, Knepper MA. 1998. Ultrastructural localization of Na-K-2Cl cotransporter in thick ascending limb and macula densa of rat kidney. Am. J. Physiol. Ren. Physiol. 275:F885–93
    [Google Scholar]
  102. 102. 
    He XR, Greenberg SG, Briggs JP, Schnermann J. 1995. Effects of furosemide and verapamil on the NaCl dependency of macula densa-mediated renin secretion. Hypertension 26:137–42
    [Google Scholar]
  103. 103. 
    Ito S, Carretero OA. 1990. An in vitro approach to the study of macula densa-mediated glomerular hemodynamics. Kidney Int 38:1206–10
    [Google Scholar]
  104. 104. 
    Lapointe JY, Laamarti A, Bell PD 1998. Ionic transport in macula densa cells. Kidney Int. 54:Suppl. 67S58–64
    [Google Scholar]
  105. 105. 
    Subramanya AR, Ellison DH. 2014. Distal convoluted tubule. Clin. J. Am. Soc. Nephrol. 9:2147–63
    [Google Scholar]
  106. 106. 
    Hierholzer K, Wiederholt M. 1976. Some aspects of distal tubular solute and water transport. Kidney Int 9:198–213
    [Google Scholar]
  107. 107. 
    Leviel F, Hübner CA, Houillier P, Morla L, El Moghrabi S et al. 2010. The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice. J. Clin. Investig. 120:1627–35
    [Google Scholar]
  108. 108. 
    Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE et al. 1996. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat. Genet. 12:24–30
    [Google Scholar]
  109. 109. 
    Bandulik S, Schmidt K, Bockenhauer D, Zdebik AA, Humberg E et al. 2011. The salt-wasting phenotype of EAST syndrome, a disease with multifaceted symptoms linked to the KCNJ10 K+ channel. Pflügers Arch 461:423–35
    [Google Scholar]
  110. 110. 
    Scholl UI, Choi M, Liu T, Ramaekers VT, Häusler MG et al. 2009. Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. PNAS 106:5842–47
    [Google Scholar]
  111. 111. 
    Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA et al. 2009. Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N. Engl. J. Med. 360:1960–70
    [Google Scholar]
  112. 112. 
    Hamilton KL, Devor DC. 2012. Basolateral membrane K+ channels in renal epithelial cells. Am. J. Physiol. Ren. Physiol. 302:F1069–81
    [Google Scholar]
  113. 113. 
    Dørup J. 1985. Ultrastructure of distal nephron cells in rat renal cortex. J. Ultrastruct. Res. 92:101–18
    [Google Scholar]
  114. 114. 
    Pacheco-Alvarez D, Cristóbal PS, Meade P, Moreno E, Vazquez N et al. 2006. The Na+:Cl cotransporter is activated and phosphorylated at the amino-terminal domain upon intracellular chloride depletion. J. Biol. Chem. 281:28755–63
    [Google Scholar]
  115. 115. 
    Estévez R, Boettger T, Stein V, Birkenhäger R, Otto E et al. 2001. Barttin is a Cl channel β-subunit crucial for renal Cl reabsorption and inner ear K+ secretion. Nature 414:558–61
    [Google Scholar]
  116. 116. 
    Thakker RV. 1999. Chloride channels in renal disease. Adv. Nephrol. Necker Hosp. 29:289–98
    [Google Scholar]
  117. 117. 
    Velázquez H, Silva T. 2003. Cloning and localization of KCC4 in rabbit kidney: expression in distal convoluted tubule. Am. J. Physiol. Ren. Physiol. 285:F49–58
    [Google Scholar]
  118. 118. 
    Hadchouel J, Delaloy C, Fauré S, Achard JM, Jeunemaitre X. 2006. Familial hyperkalemic hypertension. J. Am. Soc. Nephrol. 17:208–17
    [Google Scholar]
  119. 119. 
    Wilson FH, Disse-Nicodème S, Choate KA, Ishikawa K, Nelson-Williams C et al. 2001. Human hypertension caused by mutations in WNK kinases. Science 293:1107–12
    [Google Scholar]
  120. 120. 
    Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A et al. 2012. Mutations in Kelch-like 3 and Cullin 3 cause hypertension and electrolyte abnormalities. Nature 482:98–102
    [Google Scholar]
  121. 121. 
    Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N et al. 2012. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat. Genet. 44:456–60
    [Google Scholar]
  122. 122. 
    Subramanya AR, Liu J, Ellison DH, Wade JB, Welling PA 2009. WNK4 diverts the thiazide-sensitive NaCl cotransporter to the lysosome and stimulates AP-3 interaction. J. Biol. Chem. 284:18471–80
    [Google Scholar]
  123. 123. 
    Golbang AP, Cope G, Hamad A, Murthy M, Liu CH et al. 2006. Regulation of the expression of the Na/Cl cotransporter by WNK4 and WNK1: evidence that accelerated dynamin-dependent endocytosis is not involved. Am. J. Physiol. Ren. Physiol. 291:F1369–76
    [Google Scholar]
  124. 124. 
    Cai H, Cebotaru V, Wang YH, Zhang XM, Cebotaru L et al. 2006. WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells. Kidney Int 69:2162–70
    [Google Scholar]
  125. 125. 
    Yang CL, Angell J, Mitchell R, Ellison DH. 2003. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J. Clin. Investig. 111:1039–45
    [Google Scholar]
  126. 126. 
    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
    [Google Scholar]
  127. 127. 
    Vidal-Petiot E, Elvira-Matelot E, Mutig K, Soukaseum C, Baudrie V et al. 2013. WNK1-related Familial Hyperkalemic Hypertension results from an increased expression of L-WNK1 specifically in the distal nephron. PNAS 110:14366–71
    [Google Scholar]
  128. 128. 
    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. PNAS 110:7838–43
    [Google Scholar]
  129. 129. 
    Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K et al. 2013. Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension. Cell Rep 3:858–68
    [Google Scholar]
  130. 130. 
    Schlingmann KP, Weber S, Peters M, Nejsum LN, Vitzthum H et al. 2002. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat. Genet. 31:166–70
    [Google Scholar]
  131. 131. 
    Walder RY, Landau D, Meyer P, Shalev H, Tsolia M et al. 2002. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat. Genet. 31:171–74
    [Google Scholar]
  132. 132. 
    Pietropaolo G, Pugliese D, Armuzzi A, Guidi L, Gasbarrini A et al. 2020. Magnesium absorption in intestinal cells: evidence of cross-talk between EGF and TRPM6 and novel implications for cetuximab therapy. Nutrients 12:3277
    [Google Scholar]
  133. 133. 
    Kimura M, Usami E, Yoshimura T 2020. Effects of type of antibody to EGFR and hypomagnesemia on overall survival in first-line treatment of patients with unresectable advanced/recurrent colorectal cancer. Anticancer Res 40:7135–40
    [Google Scholar]
  134. 134. 
    Groenestege WM, Thébault S, van der Wijst J, van den Berg D, Janssen R et al. 2007. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J. Clin. Investig. 117:2260–67
    [Google Scholar]
  135. 135. 
    Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL et al. 1987. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science 237:268–75
    [Google Scholar]
  136. 136. 
    Meneton P, Loffing J, Warnock DG. 2004. Sodium and potassium handling by the aldosterone-sensitive distal nephron: the pivotal role of the distal and connecting tubule. Am. J. Physiol. Ren. Physiol. 287:F593–601
    [Google Scholar]
  137. 137. 
    Hunter RW, Ivy JR, Flatman PW, Kenyon CJ, Craigie E et al. 2015. Hypertrophy in the distal convoluted tubule of an 11β-hydroxysteroid dehydrogenase type 2 knockout model. J. Am. Soc. Nephrol. 26:1537–48
    [Google Scholar]
  138. 138. 
    Hoenderop JG, van Leeuwen JP, van der Eerden BC, Kersten FF, van der Kemp AW et al. 2003. Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5. J. Clin. Investig. 112:1906–14
    [Google Scholar]
  139. 139. 
    Hoenderop JG, van der Kemp AW, Hartog A, van de Graaf SF, van Os CH et al. 1999. Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D3-responsive epithelia. J. Biol. Chem. 274:8375–78
    [Google Scholar]
  140. 140. 
    Hoenderop JG, Nilius B, Bindels RJ. 2005. Calcium absorption across epithelia. Physiol. Rev. 85:373–422
    [Google Scholar]
  141. 141. 
    Chen L, Chou C-L, Knepper MA. 2021. Targeted single-cell RNA-seq identifies minority cell types of kidney distal nephron. J. Am. Soc. Nephrol. 32:886–96
    [Google Scholar]
  142. 142. 
    Davies JA, Davey MG. 1999. Collecting duct morphogenesis. Pediatr. Nephrol. 13:535–41
    [Google Scholar]
  143. 143. 
    Pearce D, Soundararajan R, Trimpert C, Kashlan OB, Deen PM, Kohan DE. 2015. Collecting duct principal cell transport processes and their regulation. Clin. J. Am. Soc. Nephrol. 10:135–46
    [Google Scholar]
  144. 144. 
    Roy A, Al-bataineh MM, Pastor-Soler NM 2015. Collecting duct intercalated cell function and regulation. Clin. J. Am. Soc. Nephrol. 10:305–24
    [Google Scholar]
  145. 145. 
    van den Ouweland AM, Dreesen JC, Verdijk M, Knoers NV, Monnens LA et al. 1992. Mutations in the vasopressin type 2 receptor gene (AVPR2) associated with nephrogenic diabetes insipidus. Nat. Genet. 2:99–102
    [Google Scholar]
  146. 146. 
    Gao C, Higgins PJ, Zhang W. 2020. AQP2: mutations associated with congenital nephrogenic diabetes insipidus and regulation by post-translational modifications and protein-protein interactions. Cells 9:2172
    [Google Scholar]
  147. 147. 
    García Castaño A, Pérez de Nanclares G, Madariaga L, Aguirre M, Chocron S et al. 2015. Novel mutations associated with nephrogenic diabetes insipidus: a clinical-genetic study. Eur. J. Pediatr. 174:1373–85
    [Google Scholar]
  148. 148. 
    Pearce D, Bhalla V, Funder J, Stokes J 2012. Aldosterone regulation of ion transport. Brenner and Rector's The Kidney202–25 Philadelphia: WB Saunders/Elsevier. , 9th ed..
    [Google Scholar]
  149. 149. 
    Soundararajan R, Wang J, Melters D, Pearce D 2010. Glucocorticoid-induced Leucine zipper 1 stimulates the epithelial sodium channel by regulating serum- and glucocorticoid-induced kinase 1 stability and subcellular localization. J. Biol. Chem. 285:39905–13
    [Google Scholar]
  150. 150. 
    Lu M, Wang J, Jones KT, Ives HE, Feldman ME et al. 2010. mTOR complex-2 activates ENaC by phosphorylating SGK1. J. Am. Soc. Nephrol. 21:811–18
    [Google Scholar]
  151. 151. 
    Rocchini AP. 2000. Obesity hypertension, salt sensitivity and insulin resistance. Nutr. Metab. Cardiovasc. Dis. 10:287–94
    [Google Scholar]
  152. 152. 
    Wei Y, Sun P, Wang Z, Yang B, Carroll MA, Wang WH 2006. Adenosine inhibits ENaC via cytochrome P-450 epoxygenase-dependent metabolites of arachidonic acid. Am. J. Physiol. Ren. Physiol. 290:F1163–68
    [Google Scholar]
  153. 153. 
    Zaika O, Mamenko M, O'Neil RG, Pochynyuk O. 2011. Bradykinin acutely inhibits activity of the epithelial Na+ channel in mammalian aldosterone-sensitive distal nephron. Am. J. Physiol. Ren. Physiol. 300:F1105–15
    [Google Scholar]
  154. 154. 
    Flores D, Liu Y, Liu W, Satlin LM, Rohatgi R. 2012. Flow-induced prostaglandin E2 release regulates Na and K transport in the collecting duct. Am. J. Physiol. Ren. Physiol. 303:F632–38
    [Google Scholar]
  155. 155. 
    Chambrey R, Kurth I, Peti-Peterdi J, Houillier P, Purkerson JM et al. 2013. Renal intercalated cells are rather energized by a proton than a sodium pump. PNAS 110:7928–33
    [Google Scholar]
  156. 156. 
    Alper SL, Natale J, Gluck S, Lodish HF, Brown D. 1989. Subtypes of intercalated cells in rat kidney collecting duct defined by antibodies against erythroid band 3 and renal vacuolar H+-ATPase. PNAS 86:5429–33
    [Google Scholar]
  157. 157. 
    Brown D, Hirsch S, Gluck S 1988. An H+-ATPase in opposite plasma membrane domains in kidney epithelial cell subpopulations. Nature 331:622–24
    [Google Scholar]
  158. 158. 
    Royaux IE, Wall SM, Karniski LP, Everett LA, Suzuki K et al. 2001. Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion. PNAS 98:4221–26
    [Google Scholar]
  159. 159. 
    Wall SM, Hassell KA, Royaux IE, Green ED, Chang JY et al. 2003. Localization of pendrin in mouse kidney. Am. J. Physiol. Ren. Physiol. 284:F229–41
    [Google Scholar]
  160. 160. 
    Werth M, Schmidt-Ott KM, Leete T, Qiu A, Hinze C et al. 2017. Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts. eLife 6:e24265
    [Google Scholar]
  161. 161. 
    Lake BB, Chen S, Hoshi M, Plongthongkum N, Salamon D et al. 2019. A single-nucleus RNA-sequencing pipeline to decipher the molecular anatomy and pathophysiology of human kidneys. Nat. Commun. 10:2832
    [Google Scholar]
  162. 162. 
    Wu H, Kirita Y, Donnelly EL, Humphreys BD. 2019. Advantages of single-nucleus over single-cell RNA sequencing of adult kidney: rare cell types and novel cell states revealed in fibrosis. J. Am. Soc. Nephrol. 30:23–32
    [Google Scholar]
  163. 163. 
    Stewart BJ, Ferdinand JR, Young MD, Mitchell TJ, Loudon KW et al. 2019. Spatiotemporal immune zonation of the human kidney. Science 365:1461–66
    [Google Scholar]
  164. 164. 
    Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N et al. 2012. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336:86–90
    [Google Scholar]
  165. 165. 
    Chevrier S, Levine JH, Zanotelli VRT, Silina K, Schulz D et al. 2017. An immune atlas of clear cell renal cell carcinoma. Cell 169:736–49.e18
    [Google Scholar]
  166. 166. 
    Wu H, Malone AF, Donnelly EL, Kirita Y, Uchimura K et al. 2018. Single-cell transcriptomics of a human kidney allograft biopsy specimen defines a diverse inflammatory response. J. Am. Soc. Nephrol. 29:2069–80
    [Google Scholar]
  167. 167. 
    de Leur K, Clahsen-van Groningen MC, van den Bosch TPP, de Graav GN, Hesselink DA et al. 2018. Characterization of ectopic lymphoid structures in different types of acute renal allograft rejection. Clin. Exp. Immunol. 192:224–32
    [Google Scholar]
  168. 168. 
    Zeisberg M, Kalluri R. 2015. Physiology of the renal interstitium. Clin. J. Am. Soc. Nephrol. 10:1831–40
    [Google Scholar]
  169. 169. 
    Kuppe C, Ibrahim MM, Kranz J, Zhang X, Ziegler S et al. 2021. Decoding myofibroblast origins in human kidney fibrosis. Nature 589:281–86
    [Google Scholar]
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