Differential expression of nuclear AT1receptors and angiotensin II within the kidney of the male congenic mRen2.Lewis rat

Abstract

We established a new congenic model of hypertension, the mRen2.Lewis rat and assessed the intracellular expression of angiotensin peptides and receptors in the kidney. The congenic strain was established from the backcross of the (mRen2)27 transgenic rat that expresses the mouse renin 2 gene onto the Lewis strain. The 20-wk-old male congenic rats were markedly hypertensive compared with the Lewis controls (systolic blood pressure: 195 ± 2 vs. 107 ± 2 mmHg, P < 0.01). Although plasma ANG II levels were not different between strains, circulating levels of ANG-(1–7) were 270% higher and ANG I concentrations were 40% lower in the mRen2.Lewis rats. In contrast, both cortical (CORT) and medullary (MED) ANG II concentrations were 60% higher in the mRen2.Lewis rats, whereas tissue ANG I was 66 and 84% lower in CORT and MED. For both strains, MED ANG II, ANG I, and ANG-(1–7) were significantly higher than CORT levels. Intracellular ANG II binding distinguished nuclear (NUC) and plasma membrane (PM) receptor using the ANG II radioligand125I-sarthran. Isolated CORT nuclei exhibited a high density (Bmax>200 fmol/mg protein) and affinity for the sarthran ligand ( KD<0.5 nM); the majority of these sites (>95%) were the AT1receptor subtype. CORT ANG II receptor Bmaxand KDvalues in nuclei were 75 and 50% lower, respectively, for the mRen2.Lewis vs. the Lewis rats. In the MED, the PM receptor density (Lewis: 50 ± 4 vs. mRen2.Lewis: 21 ± 5 fmol/mg protein) and affinity (Lewis: 0.31 ± 0.1 vs. 0.69 ± 0.1 nM) were lower in the mRen2.Lewis rats. In summary, the hypertensive mRen2.Lewis rats exhibit higher ANG II in both CORT and MED regions of the kidney. Evaluation of intracellular ANG II receptors revealed lower CORT NUC and MED PM AT1sites in the mRen2.Lewis. The downregulation of AT1sites in the mRen2.Lewis rats may reflect a compensatory response to dampen the elevated levels of intrarenal ANG II.