Effects of AT₁ receptor blockade on renal injury and mitogen-activated protein activity in Dahl salt-sensitive rats

Background. The mitogen-activated protein kinase (MAPK) cascade is an important intracellular mediator of angiotensin II (Ang II)-induced cell growth and differentiation. Here, we examined the effect of angiotensin II type 1 receptor (AT₁) receptor blockade on renal injury and MAPK activity in Dahl salt-sensitive (DS) rats. Methods. DS rats were maintained on a high (H: 8.0%NaCl, N = 8) or low (L: 0.3%NaCl, N = 7) salt diet, or H + candesartan cilexetil (10 to 15 mg/kg/day, N = 8). Urinary protein excretion (U _proteinV), renal cortical collagen content, and glomerular injury (assessed by semiquantitative morphometric analysis) were determined after 4-week treatments. Plasma and kidney Ang II levels were measured by radioimmunoassay. Protein levels of AT₁ and AT₂ receptors in the renal cortical tissues were analyzed by Western-blotting analyses. MAPKs activities, including extracellular signal-regulated kinases (ERK)1/2, c-Jun NH₂-terminal kinases (JNK), p38 MAPK, and BigMAPK-1 (BMK1), were measured by Western-blotting analyses or in vitro kinase assays. Results. DS/H rats showed higher mean blood pressure (MBP), U_protein V, and renal cortical collagen content than DS/L rats. Increased ERK1/2, JNK, and BMK1 activities were observed in renal cortical tissues of DS/H rats (approximately 6.3-, 4.5-, and 2.5-fold, respectively), whereas p38 MAPK activity was unchanged. Plasma Ang II levels were significantly reduced in DS/H rats compared with DS/L rats, whereas kidney Ang II contents and AT₁ receptor protein levels were similar. Candesartan did not alter MBP, but significantly reduced U_protein V and collagen content, and ameliorated progressive sclerotic and proliferative glomerular changes. Furthermore, candesartan decreased renal tissue Ang II contents (from 216 ± 19 to 46 ± 3 fmol/mL) and ERK1/2, JNK, and BMK1 activities (-45%, -60%, and -70%, respectively) in DS/H rats. Conclusion. In DS hypertensive rats, some of the renoprotective effects of AT₁ receptor blockade are accompanied by reductions in intrarenal Ang II contents and MAPK activity, which might not be mediated through arterial pressure changes.