PROGRESSION OF RENAL-FAILURE AFTER SUBTOTAL NEPHRECTOMY IN TRANSGENICRATS CARRYING AN ADDITIONAL RENIN GENE [TGR(MREN2)27]

Objective To study the evolution of glomerulosclerosis after renal abl ation in a model with abnormal regulation of the renin gene, Methods F our-month-old female ovariectomized hypertensive heterozygous transgen ic rats (TGR) harbouring the murine REN-2 gene were compared with pres sure-matched, pair-fed, stroke-prone, spontaneously hypertensive rats (SHRsp). Both groups were followed for 6 weeks after 70% subtotal neph rectomy (SNX) or sham operation. Results Blood pressures in the SNX gr oup 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 mu l/min per 100 g bo dy weight in TGR that had undergone SNX and 550 +/- 93 mu l/min per 10 0 g body weight in SHR that had undergone SNX (P < 0.02), whereas inul in clearance (C-in) in sham-operated pair-fed TGR and SHRsp controls d id 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 t hat had undergone SNX (7.48 +/- 0.79 mu m) than it was in SHRsp that h ad undergone SNX (5.27 +/- 1.38 mu m, P < 0.02). Rat renal renin messe nger RNA (mRNA) expression and, in parallel, mouse REN-2 gene expressi on 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 w as in SHRsp that had undergone SNX. The angiotensin II:I ratio in the kidney was significantly higher in TGR (P < 0.01). There wits no signi ficant difference between sham-operated or subtotally nephrectomized T GR and SHRsp with respect to angiotensin type I mRNA and angiotensinog en mRNA, The renal angiotensin converting enzyme activity, however, wa s significantly higher in sham operated and subtotally nephrectomized TGR than it was in sham operated SHRsp and in SHRsp that had undergone SNX. Conclusion Deterioration of renal function is accelerated in sub totally nephrectomized transgenic rats [TGR(mREN2)27] compared with th at in comparably hypertensive SHRsp despite suppressed circulating act ive mRNA and decreased renal renin mRNA. Although alternative explanat ions are possible, this observation is consistent with a role for loca l ANG II in the genesis of glomerulosclerosis.