title: Glucocorticoid-induced leucine zipper protein regulates sodium and potassium balance in the distal nephron.
abstract: Glucocorticoid induced leucine zipper protein (GILZ) is an aldosterone-regulated protein that controls sodium transport in cultured kidney epithelial cells. Mice lacking GILZ have been reported previously to have electrolyte abnormalities. However, the mechanistic basis has not been explored. Here we provide evidence supporting a role for GILZ in modulating the balance of renal sodium and potassium excretion by regulating the sodium-chloride cotransporter (NCC) activity in the distal nephron. Gilz-/-mice have a higher plasma potassium concentration and lower fractional excretion of potassium than wild type mice. Furthermore, knockout mice are more sensitive to NCC inhibition by thiazides than are the wild type mice, and their phosphorylated NCC expression is higher. Despite increased NCC activity, knockout mice do not have higher blood pressure than wild type mice. However, during sodium deprivation, knockout mice come into sodium balance more quickly, than do the wild type, without a significant increase in plasma renin activity. Upon prolonged sodium restriction, knockout mice develop frank hyperkalemia. Finally, in HEK293T cells, exogenous GILZ inhibits NCC activity at least in part by inhibiting SPAK phosphorylation. Thus, GILZ promotes potassium secretion by inhibiting NCC and enhancing distal sodium delivery to the epithelial sodium channel. Additionally, Gilz-/-mice have features resembling familial hyperkalemic hypertension, a human disorder that manifests with hyperkalemia associated variably with hypertension.
authors.affiliation: Division of Nephrology, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Rashmi
authors.affiliation: Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy.
authors.forename: GianLuca
authors.initials: G
authors.lastname: Colussi
authors.affiliation: Division of Nephrology, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ng
authors.affiliation: Division of Nephrology, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Xinhao
authors.initials: X
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Atif
authors.initials: A
authors.lastname: Kidwai
authors.affiliation: Division of Nephrology, Department of Medicine, University of California, San Francisco, California, USA. Electronic address: David.Pearce@ucsf.edu.
authors.forename: David
authors.initials: D
authors.lastname: Pearce
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D006947:Hyperkalemia / Q000097:blood; D006973:Hypertension / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D009399:Nephrons / Q000378:metabolism*; D010766:Phosphorylation; D011188:Potassium / Q000097:blood*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011546:Pseudohypoaldosteronism / Q000378:metabolism*; D012083:Renin / Q000097:blood / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000097:blood*; D049992:Sodium Chloride Symporters / Q000187:drug effects / Q000378:metabolism*; D064486:Solute Carrier Family 12, Member 3; D049971:Thiazides / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: C498608:Dsip1 protein, mouse; D015778:Minor Histocompatibility Antigens; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D049971:Thiazides; D014157:Transcription Factors; D012964:Sodium; C499024:Prkwnk4 protein, mouse; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498744:Wnk1 protein, mouse; D012083:Renin; D011188:Potassium
keywords: aldosterone; distal tubule; hypernatremia; potassium channels