Progression of renal failure after subtotal nephrectomy in transgenic rats carrying an additional renin gene [TGR(mREN2)27

Abstract

To study the evolution of glomerulosclerosis after renal ablation in a model with abnormal regulation of the renin gene. Four-month-old female ovariectomized hypertensive heterozygous transgenic rats (TGR) harbouring the murine REN-2 gene were compared with pressure-matched, pair-fed, stroke-prone, spontaneously hypertensive rats (SHRsp). Both groups were followed for 6 weeks after 70% subtotal nephrectomy (SNX) or sham operation. Blood pressures in the SNX group at the end of the experiment were 193 +/- 3 mmHg in TGR and 199 +/- 5 mmHg in SHRsp. The final C(in) was 306 +/- 68 microliters/min per 100 g body weight in TGR that had undergone SNX and 550 +/- 93 microliters/min per 100 g body weight in SHR that had undergone SNX (P < 0.02), whereas inulin clearance (C(in)) in sham-operated pair-fed TGR and SHRsp controls did not differ from each other. The glomerulosclerosis index was 1.75 +/- 0.08 in perfusion-fixed TGR that had undergone SNX versus 1.21 +/- 0.03 in SHR that had undergone SNX (P < 0.005). In addition, the media thickness of preglomerular vessels was significantly greater in TGR that had undergone SNX (7.48 +/- 0.79 microns) than it was in SHRsp that had undergone SNX (5.27 +/- 1.38 microns, P < 0.02). Rat renal renin messenger RNA (mRNA) expression and, in parallel, mouse REN-2 gene expression were lower in TGR after SNX. Plasma renin and angiotensin II (ANG II) concentrations were reduced to a similar extent in both SNX groups, but plasma prorenin was higher in TGR that had undergone SNX than it was in SHRsp that had undergone SNX. The angiotensin II:I ratio in the kidney was significantly higher in TGR (P < 0.01). There was no significant difference between sham-operated or subtotally nephrectomized TGR and SHRsp with respect to angiotensin type 1 mRNA and angiotensinogen mRNA. The renal angiotensin converting enzyme activity, however, was significantly higher in sham operated and subtotally nephrectomized TGR than it was in sham operated SHRsp and in SHRsp that had undergone SNX. Deterioration of renal function is accelerated in subtotally nephrectomized transgenic rats [TGR(mREN2)27] compared with that in comparably hypertensive SHRsp despite suppressed circulating active mRNA and decreased renal renin mRNA. Although alternative explanations are possible, this observation is consistent with a role for local ANG II in the genesis of glomerulosclerosis.