endothelin-1 and Hypokalemia

Acid addition to the body activates a series of homeostatic responses, one example of which is activation of NHE3, the proximal tubule Na(+)/H(+) antiporter. Feeding acid to rats increases apical membrane NHE3 abundance. Similarly, addition of acid to the media of OKP cells, a proximal tubule cell line, leads to an increase in apical membrane NHE3 activity that is due to increased trafficking of NHE3 to the apical membrane, and increased NHE3 mRNA and protein expression. Endothelins also increase NHE3 activity by inducing trafficking of NHE3 to the apical membrane, an effect mediated by the ET(B), but not the ET(A) receptor. Receptor specificity resides in the C-terminal loop and the second intracellular loop of the ET(B) receptor. In addition, the ET(B) receptor is required for acid signaling. An acid-induced signaling cascade has been defined that includes Pyk2, c-Src, ERK, c-fos, c-jun, and endothelin expression.

Topics: Acidosis; Acids; Animals; Diet; Endothelin-1; Endothelins; Hypokalemia; Kidney Tubules, Proximal; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Rats; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Sleep; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers

Hypokalemia causes renal tubulointerstitial injury with an elevation in renal endothelin-1 (ET-1). It was hypothesized that hypokalemic tubulointerstitial injury is ameliorated by the blockade of ET-A receptors (ETA), whereas ET-B receptor (ETB) antagonism may exacerbate the injury, because ETB is thought to mediate vasodilation. Rats were fed a K(+)-deficient diet alone (LC) or with an ETA-selective antagonist ABT-627 (LA) or an ETB-selective antagonist A-192621 (LB) for 8 wk. Control rats were on a normal K(+) diet alone or with the ETA-selective or ETB-selective antagonists. The severity of hypokalemia was not significantly different among LA, LB, and LC. LC developed tubulointerstitial injury with an elevation of renal preproET-1 mRNA level. There was an increase in tubular osteopontin expression, macrophage infiltration, collagen accumulation, and tubular cell hyperplasia. ETA blockade significantly ameliorated all parameters for renal injury in the cortex without suppressing local ET-1 and ETA expression. By contrast, ETB blockade significantly reduced local ET-1 and ETA expression and improved the injury to a similar extent in the cortex. In the medulla, ETA or ETB blockade only partially blocked renal injury. ETA blockade did not affect BP in normokalemic or hypokalemic rats. ETB blockade induced a BP elevation with a decrease in urinary Na(+) excretion in normokalemic but not in hypokalemic rats. These results indicate that ET-1 can mediate hypokalemic renal injury in two different ways: by directly stimulating ETA and by locally promoting endogenous ET-1 production via ETB. Thus, ETA as well as ETB blockade may be renoprotective in hypokalemic nephropathy.

Topics: Albuminuria; Animals; Atrasentan; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Hypertrophy; Hypokalemia; Kidney; Kidney Diseases; Kidney Tubules; Male; Potassium; Proteinuria; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B