To identify renally expressed genes that influence risk for hypertension, we integrated expression quantitative trait locus (QTL) analysis of the kidney with genome-wide correlation analysis of renal expression profiles and blood pressure in recombinant inbred strains derived from the spontaneously hypertensive rat (SHR). This strategy, together with renal transplantation studies in SHR progenitor, transgenic and congenic strains, identified deficient renal expression of Cd36 encoding fatty acid translocase as a genetically determined risk factor for spontaneous 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 hypertensioninduced renal injury in the rat. ( J. Clin. Invest. 1997. 100: 1373-1382.)

The mediator(s) of the adaptive increases in renal blood flow (RBF) and glomerular filtration rate (GFR) after renal mass reduction have not been identified. The present studies were designed to investigate the role of endothelium-derived nitric oxide (EDNO) in the hemodynamic adaptations after graded renal mass reduction. The experiments were performed in rats that had undergone a sham reduction in renal mass, uninephrectomy (UNX), or 5/6 NX (UNX plus excision of both poles of the contralateral kidney) 3-4 wk before. Measurements of RBF, GFR, renal vascular resistance (RVR), mean arterial pressure (MAP), and plasma renin concentration (PRC) were obtained before and after administration of the EDNO synthesis inhibitor NG-monomethyl-L-arginine (L-NMMA). L-NMMA (50 mg/kg bolus plus 500 micrograms.kg-1.min-1 infusion) led to significant (P < 0.01) and comparable increases in MAP (mmHg) (P < 0.01) in sham rats (117 +/- 6 to 154 +/- 6), UNX rats (112 +/- 5 to 139 +/- 7), and 5/6 NX rats (116 +/- 5 to 149 +/- 7). RVR increased significantly in all three groups (P < 0.01). The resultant decrease in RBF (ml.min-1.kg-1) was similar in sham rats (34.9 +/- 2.6 to 23.8 +/- 1.6), UNX rats (43.9 +/- 3.6 to 27.3 +/- 2.8), and 5/6 NX rats (34.6 +/- 2 to 22.3 +/- 1.6) (P < 0.01 for all groups).(ABSTRACT TRUNCATED AT 250 WORDS)

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Retrograde movements of urine into the renal pelvic space (pelvic refluxes) were studied in anesthetized Munich Wistar rats and hamsters. The urine was made green by a continuous i.v. infusion of lissamine green in saline, and the experimental kidney was either placed on a shallow trough or left in situ. The renal pelvis was exposed and illuminated with a fiber optic light, and urine movements were observed through the transparent but intact pelvic wall. Urine was collected from both kidneys in the rats. In both rats and hamsters, the inner medulla of the kidney was analyzed for solutes at the end of the experiment. The experimental procedures did not interfere with the normal function of the experimental kidney, and the results were the same in rats and hamsters. During constant urine flow, full refluxes did not occur. Urine either moved straight down the ureter after it exited from the ducts of Bellini or it briefly bathed the papillary tip. In rats, full pelvic refluxes started approximately 0.8 min after a bolus injection (0.5 ml of isosmotic saline, i.v.), at a time corresponding to a steep rise in urine flow (2 microliter.min-2.100 g body wt-1). Following increased infusion rate, full refluxes were associated with an increase in urine flow of 0.05 g microliter.min-2.100 g body wt-1. Full refluxes were also seen in the hamsters following a bolus injection or increased infusion rate. Increasing intrapelvic pressure by 1 cm H2O also caused full pelvic refluxes. When full refluxes occurred, urine came into contact with all areas of the renal pelvis. Because full pelvic refluxes occur only during rising urine flow, this mechanism would bring urine with decreasing osmolality into contact with the outer medullary areas facing the pelvic space.

Linkage studies in the fawn-hooded hypertensive rat have suggested that genes influencing susceptibility to hypertension-associated renal failure may exist on rat chromosome 1q. To investigate this possibility in a widely used model of hypertension, the spontaneously hypertensive rat (SHR), we compared susceptibility to hypertension-induced renal damage between an SHR progenitor strain and an SHR congenic strain that is genetically identical except for a defined region of chromosome 1q. Backcross breeding with selection for the markers D1Mit3 and Igf2 on chromosome 1 was used to create the congenic strain (designated SHR.BN-D1Mit3/Igf2) that carries a 22 cM segment of chromosome 1 transferred from the normotensive Brown Norway rat onto the SHR background. Systolic blood pressure (by radiotelemetry) and urine protein excretion were measured in the SHR progenitor and congenic strains before and after the induction of accelerated hypertension by administration of DOCA-salt. At the same level of DOCA-salt hypertension, the SHR.BN-D1Mit3/Igf2 congenic strain showed significantly greater proteinuria and histologically assessed renal vascular and glomerular injury than the SHR progenitor strain. These findings demonstrate that a gene or genes that influence susceptibility to hypertension-induced renal damage have been trapped in the differential chromosome segment of the SHR.BN-D1Mit3/Igf2 congenic strain. This congenic strain represents an important new model for the fine mapping of gene(s) on chromosome 1 that affect susceptibility to hypertension-induced renal injury in the rat.

Functional renal compensatory hypertrophy (RCH) in the uninephrectomized rat is completely reversible by transplantation in Brown Norway (BN) rats, while anatomic RCH is not. To determine the nephron element(s) responsible for persistent anatomic RCH, we performed morphometric analysis on perfusion fixed rat kidneys following renal function studies. In this model the function of renal transplants is not different from contralateral and unmanipulated control kidneys, and there is no histological evidence of rejection. Rats uninephrectomized for three or six weeks had larger glomeruli than controls, and after transplantation of a previously hypertrophied kidney into a rat with a normal or a solitary hypertrophied kidney, glomerular size returned to control levels. Increased glomerular capillary volume (CVCP) in kidneys with RCH was due to increased capillary length (LCP; 13.1 +/- 1.0 mm cf. 10.3 +/- 0.9, P < 0.01) without increase in capillary radius (RCP; 3.26 +/- 0.33 microM cf. 3.28 +/- 0.24). In contrast, return of CVCP to control levels in kidneys undergoing regression was associated with persistently elevated LCP (13.0 +2- 2.9 mm; native previously hypertrophied kidney; 12.2 +/- 0.9; transplanted previously hypertrophied kidney vs. 10.3 +/- 0.9, P < 0.01) and decreased RCP (2.79 +/- 0.10 microM and 2.73 +/- 0.09, cf 3.28 +/- 0.24, P < 0.01). RCH was associated with proportional increases in glomerular, tubular, and vascular-interstitial volumes while only elevated tubular volume persisted during regression. Altered glomerular capillary dimensions and increased tubular volumes acquired during renal RCH induced by unilateral nephrectomy persisted during complete functional regression.(ABSTRACT TRUNCATED AT 250 WORDS)

These data unequivocally demonstrate that the SHRsp kidneys are intrinsically more susceptible than the SHR kidneys to renal damage when exposed to exactly the same BP and metabolic environment.