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2017 ; 91
(5
): 1159-1177
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Glucocorticoid-induced leucine zipper protein regulates sodium and potassium
balance in the distal nephron
#MMPMID28094030
Rashmi P
; Colussi G
; Ng M
; Wu X
; Kidwai A
; Pearce D
Kidney Int
2017[May]; 91
(5
): 1159-1177
PMID28094030
show ga
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.