Nephroprotection of an ET _A -Receptor Blocker (LU 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats

Abstract

Abstract-The present study was designed to assess whether the orally active and highly specific endothelin A (ET A ) receptor antagonist LU 135252 affects progressive renal dysfunction in a hypertensive rat model of renal damage, ie, the uninephrectomized (UNX) stroke-prone spontaneously hypertensive rat (SHRsp). The animals were examined on a normal salt (0.25%) diet and, to sensitize the kidney to hypertensive injury, also on a high salt (3%) diet. Stereological methods were used to quantify indices of glomerulosclerosis, vascular damage, and tubulointerstitial damage. Treatment with LU 135252 (100 mg/kg body wt) did not affect systolic blood pressure (BP) in animals on a normal salt diet during the whole period of the experiment (18 weeks) or in salt-loaded animals until week 10; subsequently, BP was slightly but significantly lower in salt-loaded UNX-SHRsp given LU 135252. Between weeks 6 and 12, 40% of the untreated UNX-SHRsp on a high salt diet, but none on a standard salt diet, died; such mortality was completely prevented by LU 135252. Indices of renal damage were more abnormal in salt-loaded UNX-SHRsp compared with UNX-SHRsp on a normal salt diet. Development of glomerulosclerosis and tubulointerstitial and vascular damage in UNX-SHRsp on high salt was completely prevented by LU 135252. The respective indices were no longer significantly different from those of salt-loaded sham-operated SHRsp controls. In the less severely damaged kidneys of UNX-SHRsp on normal salt, treatment with LU 135252 tended to ameliorate the indices, but the difference was not statistically significant. The results document a role of the ET system, specifically of ET A receptors, in the development of progressive renal injury in salt-loaded UNX-SHRsp. LU 135252 completely prevented death and renal damage resulting from salt loading.(Hypertension. 1998;31:995-1001.)

Different Contributions of Endothelin-A and Endothelin-B Receptors in the Pathogenesis of Deoxycorticosterone Acetate–Salt–Induced Hypertension in Rats

“…Nephroprotective effects of chronic treatment with ET A -selective receptor antagonists have been noted using LU 135252 in stroke-prone spontaneously hypertensive rats 27 and using A-127722 in Dahl salt-sensitive rats. 8 In the present study, we also noted that treatment with ABT-627 markedly improved both glomerular and tubular functions in DOCA-salt hypertensive rats.…”

Renal Endothelin ET A /ET B Receptor Imbalance Differentiates Salt-Sensitive From Salt-Resistant Spontaneous Hypertension

“…Moreover, these data could, at least in part, explain the strong nephroprotective effect of selective ET A receptor blockade in another SHRSP-NX-NaCl model reported previously. 6 Finally, increased renal ET-1 levels, as indicated by higher renal ET-1 mRNA expression and urinary ET-1 excretion in our SHRSP-NX-NaCl model, may therefore stimulate sodium reabsorption by ENaC via the increased renal ET A /ET B receptor ratio. Although it is well established that the nephron represents a major site for intrarenal ET-1 production and ET-1 binding, 19 we cannot deduce from the current set of experiments where the induction of renal ET-1 and ET A receptor occurred in the SHRSP-NX-NaCl model.…”

“…6 In addition, we observed a significant elevation in U p and U alb , indicating manifestation of renal damage in SHRSP-NXNaCl. In contrast, no increase in SBP or any significant changes in C crea , GSI, TDI, U P , or U alb were observed in SHR-NX-NaCl.…”

“…13 Because we investigated only a single time point (6 weeks after nephrectomy and high-sodium diet), it is difficult to distinguish the effect of high blood pressure from activation of the renal ET system on development of renal damage in our experiment. Nevertheless, Orth and coworkers 6 clearly demonstrated in their work that the nephroprotective effect of selective ET A receptor blockade in the SHRSP-NX-NaCl model was independent of high blood pressure, which led to the conclusions that ET plays a crucial role in progressive renal injury and that the progression-promoting effects are mainly mediated via the ET A receptor. ECE-1 gene expression was not altered by NX-NaCl in SHR or SHRSP, suggesting that the regulation of ECE-1, at least at the mRNA level, is not relevant for the development of SS-SH and renal damage in the SHRSP-NX-NaCl model.…”

“…Most studies did not investigate the regulation of ET receptor subtypes in the kidney through the direct determination of receptor density and affinity but rather draw indirect conclusions from the application of selective or unselective ET receptor antagonists. Recently, Orth et al 6 reported on a striking salutary effect of chronic ET A receptor blockade with complete normalization of kidney damage in uninephrectomized stroke-prone spontaneously hypertensive rats (SHRSP) after high-salt diet. Interestingly, this finding was independent of an antihypertensive effect of the compound.…”