Monique C. Churchill

Previously, it was shown that 5/6 renal mass reduction by surgical excision (RK-NX) results in a marked reduction of glomerulosclerosis (GS) at 6 wk compared with the conventional 5/6 renal ablation by infarction (RK-I) model. To determine the pathogenetic correlates of the striking differences in GS, radiotelemetrically measured BP; single nephron function; glomerular volume; the temporal expression of mRNA for renin, transforming growth factor-beta, and platelet-derived growth factor-B; and plasma renin concentration were compared between RK-NX, RK-I, and sham-operated control rats. Hypertension only developed in the RK-I model, was present at 3 d after infarction, and was correlated with both an increased expression of renin mRNA by Northern analysis and elevated plasma renin concentration. Structural (glomerular volume) and functional (single nephron blood flow and GFR) indices of the compensatory adaptive response were significantly but similarly increased in the RK-NX and RK-I rats compared with sham-operated controls, indicating that these adaptations per se are not responsible for the initiation of GS after 5/6 renal mass reduction. Glomerular capillary pressure (P(GC)) was also significantly increased in both RK-I (56 +/- 2 mmHg) and RK-NX rats (50 +/- 0.9 mmHg) compared with controls (46 +/- 0.8 mmHg, P < 0.01), but the increase was significantly greater in RK-I versus RK-NX rats (P < 0.05) consistent with the higher BP in RK-I rats. These data indicate that differences in renin probably account for the early divergence of BP (and P(GC)) responses between RK-I and RK-NX models. Transforming growth factor-beta and platelet-derived growth factor-B mRNA expression in pooled RNA from kidneys from each group showed increases at 21 d along with early evidence of glomerular injury in the RK-I group but not in the RK-NX group, consistent with their postulated roles as molecular mediators of GS, but only in rats with pathologic glomerular hypertension.

To test the hypothesis that genetic factors can determine susceptibility to hypertension-induced renal damage, we derived an experimental animal model in which two genetically different yet histocompatible kidneys are chronically and simultaneously exposed to the same blood pressure profile and metabolic environment within the same host. Kidneys from normotensive Brown Norway rats were transplanted into unilaterally nephrectomized spontaneously hypertensive rats (SHR-RT1.N strain) that harbor the major histocompatibility complex of the Brown Norway strain. 25 d after the induction of severe hypertension with deoxycorticosterone acetate and salt, proteinuria, impaired glomerular filtration rate, and extensive vascular and glomerular injury were observed in the Brown Norway donor kidneys, but not in the SHR-RT1.N kidneys. Control experiments demonstrated that the strain differences in kidney damage could not be attributed to effects of transplantation-induced renal injury, immunologic rejection phenomena, or preexisting strain differences in blood pressure. These studies (a) demonstrate that the kidney of the normotensive Brown Norway rat is inherently much more susceptible to hypertension-induced damage than is the kidney of the spontaneously hypertensive rat, and (b) establish the feasibility of using organ-specific genome transplants to map genes expressed in the kidney that determine susceptibility to hypertension-induced renal injury in the rat.