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Deprecated: Implicit conversion from float 276.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Am+J+Physiol+Renal+Physiol 2015 ; 308 (6): F522-34 Nephropedia Template TP
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Estrogen directly and specifically downregulates NaPi-IIa through the activation of both estrogen receptor isoforms (ER? and ER?) in rat kidney proximal tubule #MMPMID25608964
Burris D; Webster R; Sheriff S; Faroqui R; Levi M; Hawse JR; Amlal H
Am J Physiol Renal Physiol 2015[Mar]; 308 (6): F522-34 PMID25608964show ga
We have previously demonstrated that estrogen (E2) downregulates phosphate transporter NaPi-IIa and causes phosphaturia and hypophosphatemia in ovariectomized rats. In the present study, we examined whether E2 directly targets NaPi-IIa in the proximal tubule (PT) and studied the respective roles of estrogen receptor isoforms (ER? and ER?) in the downregulation of NaPi-IIa using both in vivo and an in vitro expression systems. We found that estrogen specifically downregulates NaPi-IIa but not NaPi-IIc or Pit2 in the kidney cortex. Proximal tubules incubated in a ?shake? suspension with E2 for 24 h exhibited a dose-dependent decrease in NaPi-IIa protein abundance. Results from OVX rats treated with specific agonists for either ER? [4,4?,4?;-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol, PPT] or ER? [4,4?,4?-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol, DPN] or both (PPT + DPN), indicated that only the latter caused a sharp downregulation of NaPi-IIa, along with significant phosphaturia and hypophosphatemia. Lastly, heterologous expression studies demonstrated that estrogen downregulated NaPi-IIa only in U20S cells expressing both ER? and ER?, but not in cells expressing either receptor alone. In conclusion, these studies demonstrate that rat PT cells express both ER? and ER? and that E2 induces phosphaturia by directly and specifically targeting NaPi-IIa in the PT cells. This effect is mediated via a mechanism involving coactivation of both ER? and ER?, which likely form a functional heterodimer complex in the rat kidney proximal tubule.