Pendrin a possible new target for diuretic therapy

By Stephanie Leveene

In patients with fluid overload, inhibition of the chloride-absorbing transporter pendrin and the NaCl co-transporter (NCC) may provide an effective diuretic regimen without triggering hypokalemia, research suggests.

Pendrin and the thiazide target NCC are both expressed on distal convoluted tubule cells. The single deletion of pendrin or NCC does not cause salt wasting under basal conditions, but studies have found that pendrin knockout (KO) and NCC KO mice had volume depletion or developed hypotension during periods of salt restriction. This suggests that pendrin and NCC are active primarily during salt depletion and/or in response to increased aldosterone levels.

Manoocher Soleimani (University of Cincinnati, Ohio, USA) therefore studied double-KO pendrin and NCC mice to see if pendrin and NCC compensate for loss of each other under basal conditions, perhaps hiding the function that each compound has in salt reabsorption.

Results are reported in the Proceedings of the National Academy of Sciences. The pendrin and NCC double KO mice had extensive salt wasting and renal water as well as serious renal failure, volume depletion, and metabolic alkalosis. When these mice were put on a high-salt diet for 7 days, their vascular volume depletion and metabolic alkalosis greatly improved.

Thiazides are the most commonly used diuretic because they are relatively mild and do not cause excessive salt wasting. However, the mild salt wasting effect of thiazides is disproportionate to the amount of NCC inhibition; therefore, other salt-absorbing transporters near NCC might be compensating and thus reducing the diuretic effect of thiazides.

Previous evidence indicates, and the current study confirms, that pendrin plays an important role in salt absorption when NCC is not active. The investigators conclude that "functional pendrin blunts the diuretic effect of NCC inhibition subsequent to treatment with thiazides by compensatory absorption of salt in the distal nephron."

In a press release which accompanied the article, Soleimani said that these findings could provide the basis for targeted diuretic therapy that inhibits pendrin for patients who may not respond well to thiazides: "By giving a pendrin inhibitor in conjunction with thiazide, a mild diuretic, it could greatly relieve fluid retention, providing another treatment option and improving patient outcomes."

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