Aldosterone regulates Na+, K+ ATPase activity in human renal proximal tubule cells through mineralocorticoid receptor

Abstract

The mechanisms by which aldosterone increases Na(+), K(+) ATPase and sodium channel activity in cortical collecting duct and distal nephron have been extensively studied. Recent investigations demonstrate that aldosterone increases Na-H exchanger-3 (NHE-3) activity, bicarbonate transport, and H(+) ATPase in proximal tubules. However, the role of aldosterone in regulation of Na(+), K(+) ATPase in proximal tubules is unknown. We hypothesize that aldosterone increases Na(+), K(+) ATPase activity in proximal tubules through activation of the mineralocorticoid receptor (MR). Immunohistochemistry of kidney sections from human, rat, and mouse kidneys revealed that the MR is expressed in the cytosol of tubules staining positively for Lotus tetragonolobus agglutinin and type IIa sodium-phosphate cotransporter (NpT2a), confirming proximal tubule localization. Adrenalectomy in Sprague-Dawley rats decreased expression of MR, ENaC α, Na(+), K(+) ATPase α1, and NHE-1 in all tubules, while supplementation with aldosterone restored expression of above proteins. In human kidney proximal tubule (HKC11) cells, treatment with aldosterone resulted in translocation of MR to the nucleus and phosphorylation of SGK-1. Treatment with aldosterone also increased Na(+), K(+) ATPase-mediated (86)Rb uptake and expression of Na(+), K(+) ATPase α1 subunits in HKC11 cells. The effects of aldosterone on Na(+), K(+) ATPase-mediated (86)Rb uptake were prevented by spironolactone, a competitive inhibitor of aldosterone for the MR, and partially by Mifepristone, a glucocorticoid receptor (GR) inhibitor. These results suggest that aldosterone regulates Na(+), K(+) ATPase in renal proximal tubule cells through an MR-dependent mechanism.

The influence of spironolactone on the serum electrolytes balance and renal cortical magnesium and calcium contents in cisplatin – treated rabbits

“…Moreover, some investigators have indicated that expression of the tubular Na + , K + -ATPase was up-regulated by the aldosterone treatment and was suppressed by spironolactone. 25 Similar ameliorative effects of spironolactone were also observed with other nephrotoxic drugs. Spironolactone was shown to prevent hypokalemia by reducing urinary potassium loss in patients treated with amphotericin B.…”

Csk Regulates Blood Pressure by Controlling the Synthetic Pathways of Aldosterone

“…Of the 2 main effectors of sodium reabsorption, NKAs increase in activity and number in response to aldosterone, whereas ENaCs undergo early activation but experience a slow rise in number. 39, 40 In our results, the total amount of ENaCα/β did not increase in Csk +/− , implying that aldosterone-induced Sgk1 affects only the activity of ENaCs, not their expression level. 41 The upregulation of NKAα suggests that transcellular movement of sodium is facilitated by aldosteroneinduced NKAs in Csk +/− .…”

“…41 The upregulation of NKAα suggests that transcellular movement of sodium is facilitated by aldosteroneinduced NKAs in Csk +/− . 40 Treatment with PP2 partially reversed the increase in Sgk1 and NKAα to wild-type levels, likely due to a delayed effect throughout the synthesis of steroidogenic enzymes and the degradation of accumulated proteins.…”

PLAGL1 protein is differentially expressed in the nephron segments and collecting ducts in human kidney

“…The hypothetical involvement of PLAGL1 in the control of both calcium reabsorption and aldosterone-regulated sodium-potassium transport can be supported by the fact that segments of the uriniferous tubule known as localization for these processes [21,22] overlap with the pattern of PLAGL1 expression observed in the present study. It was also documented that aldosterone-activated mineralocorticoid receptors can influence the expression of sodium bicarbonate transporters SLC9A3 and Na + / /K + -ATPase subunit alpha in the epithelial cells of proximal tubule [23]. PLAGL1-binding sequences were found in the promoter of SLC2A1 gene encoding for GLUT1 transporter which is present in the basolateral membrane of the proximal tubule epithelial cells [24].…”