a-192621 and Proteinuria

Excessive production of fibrosis is a feature of hypertension-induced renal injury. Activation of RhoA/Rho-kinase (ROCK) axis has been shown in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We assessed whether selective endothelin receptor blockers can attenuate renal fibrosis by inhibiting RhoA/ROCK axis in DOCA-salt rats.. At 4 weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 4 weeks: vehicle, ABT-627 (endothelin-A receptor inhibitor) and A192621 (endothelin-B receptor inhibitor).. DOCA-salt was characterized by increased blood pressure, decreased renal function, increased proteinuria, increased glomerulosclerosis and tubulointerstitial fibrosis with myofibroblast accumulation, increased renal endothelin-1 levels and RhoA activity along with increased expression of connective tissue growth factor at both mRNA and protein levels as compared with uninephrectomized control male Wistar rats. Treatment with a selective mineralocorticoid receptor antagonist, eplerenone, ameliorated proteinuria. Impaired renal function and histological changes were overcome by treatment with ABT-627, but not with A192621. The beneficial effects of bosentan, a nonspecific endothelin receptor blocker, on proteinuria, RhoA activity, and connective tissue growth factor levels were similar to ABT-627. Furthermore, in an isolated perfuse kidney, a RhoA inhibitor, C3 exoenzyme, and two ROCK inhibitors, fasudil and Y-27632, significantly attenuated connective tissue growth factor levels.. These results indicate that DOCA-salt elevates renal endothelin-1 levels and RhoA activity via activation of mineralocorticoid receptor, resulting in renal fibrosis and proteinuria. Endothelin-A receptor blockade can attenuate DOCA-salt-induced renal fibrosis probably through the inhibition of RhoA/ROCK activity and connective tissue growth factor expression.

Topics: Animals; Atrasentan; Blood Pressure; Desoxycorticosterone Acetate; Endothelin Receptor Antagonists; Endothelin-1; Fibrosis; Gene Expression Regulation; Hypertension; Kidney; Male; Proteinuria; Pyrrolidines; Random Allocation; Rats; Rats, Wistar; rho-Associated Kinases; rhoA GTP-Binding Protein; Sodium Chloride, Dietary

Female rats are more resistant to blood pressure increases induced by high salt (HS) intake or angiotensin (Ang) II infusion. Because endothelin ET(B) receptors on endothelial and epithelial cells mediate tonic vasodilation and sodium excretion, we hypothesized that ET(B) receptors limit the hypertensive response and renal injury induced by HS diet alone or with chronic AngII infusion (AngII/HS) in female compared with male rats. A 4 week HS diet (4% NaCl) did not significantly change blood pressure (measured by telemetry) in either male or female Sprague-Dawley rats. Administration of the ET(B) receptor antagonist A-192621 (1, 3 and 10 mg/kg per day in food) during HS feeding caused a dose-dependent increase in blood pressure in both sexes. In AngII/HS rats, males had a larger increase in blood pressure than females. The increase in blood pressure produced by ET(B) receptor blockade in male AngII/HS rats was not significant. However, A-192621 treatment resulted in a significant further increase in blood pressure in female AngII/HS rats. Male rats had consistently higher protein excretion rates before and during AngII/HS, but this was not significantly affected by ET(B) receptor blockade in either sex. In conclusion, ET(B) receptors play a significantly greater beneficial role in protecting female compared with male rats against AngII-induced hypertension and may contribute to the sex differences in AngII-induced hypertension.

Topics: Angiotensin II; Animals; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dose-Response Relationship, Drug; Drug Synergism; Endothelin B Receptor Antagonists; Female; Hypertension; Male; Proteinuria; Pyrrolidines; Rats; Receptor, Endothelin B; Sex Characteristics; Sodium Chloride, Dietary

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