Genetic susceptibility to renal injury in hypertension.

Substantial evidence indicates that hypertension plays a predominant role in the progression of most chronic renal diseases including diabetic nephropathy. Nevertheless, significant differences are observed in the susceptibility to develop hypertension-associated renal damage between individuals, racial groups and animal strains despite comparable hypertension. Recent studies employing a variety of genetic methods both in humans and in experimental models, have provided strong support for the potential importance of genetic factors and have suggested that genes influencing susceptibility to renal damage may be inherited separately from genes that influence blood pressure. However, due to the genetic complexity involved in a multifactorial trait such as the susceptibility to hypertensive renal damage, very limited progress has been achieved thus far in attempts to link such susceptibility to specific genetic mechanisms, chromosome regions and/or candidate genes. It is anticipated that the rapid recent advances in molecular genetic techniques and the simultaneous use of multiple complementary strategies, as is currently under way, will greatly facilitate this search and provide fundamental new insights into the pathogenesis of hypertensive renal damage.

Kidney-specific chromosome transfer in genetic hypertension: the Dahl hypothesis revisited.

BACKGROUND: A central dogma in the field of essential hypertension research is that the genetic transmission of increased blood pressure is determined solely by the genotype of the kidney. This concept is based in large part on studies in experimental rat models of spontaneous hypertension in which transplantation of a kidney from a hypertensive strain into a normotensive strain was reported to increase blood pressure, and transplantation of a kidney from a normotensive strain into a hypertensive strain was reported to decrease blood pressure. The enduring interpretation of these now classic experiments remains virtually unchanged from the view originally espoused a quarter century ago by Lewis Dahl, one of the founding fathers of the field of genetic hypertension research: "Blood pressure is determined by the genotype of the donor kidney and not the genotype of the recipient." METHODS: To test the Dahl hypothesis, we determined the blood pressure effects of selective intrarenal versus extrarenal exchange of single chromosome regions between the spontaneously hypertensive rat (SHR) and the normotensive Brown Norway (BN) rat. RESULTS: The replacement of a defined segment of chromosome 1 in the SHR with the corresponding chromosome region of the BN rat was sufficient to attenuate hypertension when selectively achieved either inside the kidney or outside the kidney. CONCLUSIONS: The current finding (1) demonstrates that naturally occurring genetic variants exist that can regulate blood pressure when selectively expressed outside the kidney as well as inside the kidney, and (2) compels reconsideration of the long-held view that in essential hypertension, the genetic transmission of increased blood pressure is determined solely by the genotype of the kidney.

Differential salt-sensitivity in the pathogenesis of renal damage in SHR and stroke prone SHR.

The spontaneously hypertensive rat (SHR) and the stroke prone SHR (SHRsp) display contrasting susceptibilities to the development of the severe hypertensive lesions of malignant nephrosclerosis, both with aging and after the provision of a high salt intake on the background of a Japanese style "stroke prone" rodent diet. The SHR is relatively resistant, whereas the SHRsp is markedly susceptible. The responsible mechanisms remain controversial. Blood pressure (BP) radiotelemetry was used to investigate the interrelationship between salt intake, systolic BP, and renal damage in 8- to 12-week-old male SHR and SHRsp given a standard North American style diet for 6 weeks, a standard diet plus 1% NaCl as drinking water for 6 weeks, or an 8% NaCl diet plus tap water for 4 weeks. After 4 weeks, BP was significantly greater in the SHRsp compared to the SHR and was significantly more sensitive to supplemental salt in the SHRsp than in SHR. Average systolic pressures during week 5 (after 4 weeks on standard diet plus tap water, standard diet plus 1% NaCl, and 8% NaCl diet plus tap water) were 188.0 +/- 3.0 mm Hg, 207.3 +/- 5.6 mm Hg, and 226 +/- 9.4 mm Hg in SHRsp compared with 171.4 +/- 3.8 mm Hg, 180.6 +/- 3.8 mm Hg, and 190.3 +/- 5.0 mm Hg in SHR. In the absence of supplemental NaCl, both strains exhibited minimal evidence of hypertensive renal damage until about 16 weeks of age. A high salt intake resulted in the development of lesions of malignant nephrosclerosis (fibrinoid necrosis and thrombosis of small vessels and glomeruli) in the SHRsp but not in the SHR; semiquantitative histologic renal damage scores in SHRsp versus SHR being 10.4 +/- 2.0 versus 0.7 +/- 0.2 after 6 weeks of standard diet plus 1% NaCl, and 32.1 +/- 2.5 versus 0.7 +/- 0.4 after 4 weeks of 8% NaCl diet plus tap water; P < .001 for both comparisons. The development of more severe hypertension in salt-supplemented SHRsp could only partly account for the severity of renal damage in SHRsp, the increase in which was disproportionate to the increase in absolute BP. However, the rate of increase of BP was greater in the SHRsp and this might have contributed to the greater renal damage observed in the SHRsp. These data indicate that the contrasting genetic susceptibility to renal damage between SHR and SHRsp is mediated, at least in part, by a differential BP salt sensitivity.

Heart failure alters the strength and mechanisms of the muscle metaboreflex.

We hypothesized that excessive sympathoactivation observed during strenuous exercise in subjects with heart failure (HF) may result from tonic activation of the muscle metaboreflex (MMR) via hypoperfusion of active skeletal muscle. We studied MMR responses in dogs during treadmill exercise by graded reduction of terminal aortic blood flow (TAQ) before and after induction of HF by rapid ventricular pacing. At a low workload, in both control and HF experiments, large decreases in TAQ were required to elicit the MMR pressor response. During control experiments, this pressor response resulted from increased cardiac output (CO), whereas in HF CO did not increase; thus the pressor response was solely due to peripheral vasoconstriction. In HF, MMR activation also induced higher plasma levels of vasopressin, norepinephrine (NE), and renin. At a higher workload, in control experiments any reduction of TAQ elicited MMR pressor responses. In HF, before any vascular occlusion, TAQ was already below MMR control threshold levels and reductions in TAQ again did not result in higher CO; thus SAP increased via peripheral vasoconstriction. NE rose markedly, indicating intense sympathetic activation. We conclude that in HF, the MMR is likely tonically active at moderate workloads and contributes to the tonic sympathoactivation.

The effects of housing enrichment on cardiovascular parameters in spontaneously hypertensive rats.

By using radiotelemetry, we measured blood pressure, heart rate, and locomotor activity in adult male spontaneously hypertensive (SHR) rats during three consecutive periods in which they received various social and non-social cage enrichments. The objective was to determine whether these enriching experiences would affect cardiovascular parameters. During the first period, the readings from four individually housed males, each with a telemetry transmitter in the abdominal cavity and connected to a femoral artery catheter, were compared to those from five similarly instrumented rats that were each housed with another rat. Systolic blood pressure and activity but not diastolic blood pressure or heart rate were higher in rats housed with another rat compared to those housed alone. During the second period, each cage of animals was enriched by including a large piece of plastic drainpipe and several golf balls. In addition, the nine animals were placed together daily for two hours at the beginning of the dark phase of the photoperiod in a large, three-tiered enclosure containing a running wheel, several lengths of plastic drainpipe, and multiple golf balls. Systolic and diastolic blood pressures but not heart rate or activity were higher in the double-housed rats than those housed alone. During the last period, the rats previously housed with another rat were switched to single housing, and those previously housed alone were placed with another rat. The daily activity and cage enrichments were otherwise continued. Removal of a cage mate increased systolic blood pressure, diastolic blood pressure, and heart rate but not activity compared parameters in animals that were changed from single to double housing. During the entire experiment, activity and all cardiovascular parameters were increased during the dark phase compared to the light phase of the daily photoperiod. However, there was no statistically significant correlation between these circadian changes and the housing conditions. In summary, providing social enrichment in the form of another rat or non-social cage enrichment combined with a daily period of group housing and physical activity increased diastolic and/or systolic blood pressure of SHR rats. In addition, the loss of continuous social enrichment increased blood pressure and heart rate even when the other enrichments were continued. These changes were not always related to increased activity in the cage.

Genetic isolation of a chromosome 1 region affecting susceptibility to hypertension-induced renal damage in the spontaneously hypertensive rat.

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.

Genetics of Cd36 and the clustering of multiple cardiovascular risk factors in spontaneous hypertension.

Disorders of carbohydrate and lipid metabolism have been reported to cluster in patients with essential hypertension and in spontaneously hypertensive rats (SHRs). A deletion in the Cd36 gene on chromosome 4 has recently been implicated in defective carbohydrate and lipid metabolism in isolated adipocytes from SHRs. However, the role of Cd36 and chromosome 4 in the control of blood pressure and systemic cardiovascular risk factors in SHRs is unknown. In the SHR. BN-Il6/Npy congenic strain, we have found that transfer of a segment of chromosome 4 (including Cd36) from the Brown Norway (BN) rat onto the SHR background induces reductions in blood pressure and ameliorates dietary-induced glucose intolerance, hyperinsulinemia, and hypertriglyceridemia. These results demonstrate that a single chromosome region can influence a broad spectrum of cardiovascular risk factors involved in the hypertension metabolic syndrome. However, analysis of Cd36 genotypes in the SHR and stroke-prone SHR strains indicates that the deletion variant of Cd36 was not critical to the initial selection for hypertension in the SHR model. Thus, the ability of chromosome 4 to influence multiple cardiovascular risk factors, including hypertension, may depend on linkage of Cd36 to other genes trapped within the differential segment of the SHR. BN-Il6/Npy strain.

Effect of chromosome 19 transfer on blood pressure in the spontaneously hypertensive rat.

Linkage studies in the spontaneously hypertensive rat (SHR) have suggested that a gene or genes regulating blood pressure may exist on rat chromosome 19 in the vicinity of the angiotensinogen gene. To test this hypothesis, we measured blood pressure in SHR progenitor and congenic strains that are genetically identical except for a segment of chromosome 19 containing the angiotensinogen gene transferred from the normotensive Brown Norway (BN) strain. Transfer of this segment of chromosome 19 from the BN strain onto the genetic background of the SHR induced significant decreases in systolic and diastolic blood pressures in the recipient SHR chromosome 19 congenic strain. To test for differences in angiotensinogen gene expression between the congenic and progenitor strains, we measured angiotensinogen mRNA levels in a variety of tissues, including aorta, brain, kidney, and liver. We found no differences between the progenitor and congenic strains in the angiotensinogen coding sequence or in angiotensinogen expression that would account for the blood pressure differences between the strains. In addition, no significant differences in plasma levels of angiotensinogen or plasma renin activity were detected between the 2 strains. Thus, transfer of a segment of chromosome 19 containing angiotensinogen from the BN rat into the SHR induces a decrease in blood pressure without inducing any major changes in plasma angiotensinogen levels or plasma renin activity. These results indicate that the differential chromosome segment trapped in the SHR chromosome 19 congenic strain contains a quantitative trait locus that influences blood pressure in the SHR but that this blood pressure effect is not explained by differences in plasma angiotensinogen levels or angiotensinogen expression.

Substantial cardiac parasympathetic activity exists during heavy dynamic exercise in dogs.

We investigated the extent of functional parasympathetic and sympathetic activity to the heart at rest and during mild to heavy dynamic exercise in conscious dogs. The animals were chronically instrumented to monitor mean arterial pressure (MAP), heart rate (HR), and terminal aortic blood flow (TAQ) and trained to run on a motor-driven treadmill. MAP, HR, and TAQ were monitored at rest and during steady-state dynamic exercise ranging from mild [3.2 kilometers per hour (kph), 0% grade] to heavy exercise (8 kph, 15% grade). Experiments were performed before and after blocking the effects of either the parasympathetic nerves (atropine 0.2 mg/kg i.v.) or sympathetic nerves (atenolol 2.0 mg/kg i.v.) to the heart. In addition, blood samples were taken at rest and at steady state during exercise, and plasma levels of vasopressin and renin activity were assessed. At rest and during all levels of exercise, muscarinic cholinergic receptor blockade caused a marked increase in HR over control (saline treated) levels with little effect on MAP or TAQ. beta-Adrenergic receptor blockade had no significant effect on HR at rest and during mild exercise. At moderate to heavy workloads, beta-receptor blockade significantly reduced MAP, HR, and TAQ and increased plasma vasopressin levels. We conclude that, even during heavy dynamic exercise, significant functional parasympathetic tone to the heart exists. Thus, over a wide range of exercise workloads, HR is under the tonic control of both sympathetic and parasympathetic nerves.

Genetic susceptibility to hypertension-induced renal damage in the rat. Evidence based on kidney-specific genome transfer.

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.

Kallikrein excretion in Dahl salt-sensitive and salt-resistant rats with native and transplanted kidneys.

Urinary kallikrein excretion is decreased in Dahl salt-sensitive (S) vs. salt-resistant (R) rats, and several lines of reasoning suggest not only that decreased kallikrein excretion is a marker for salt-sensitive hypertension but also that kallikrein might play a pathogenic role. Because previous cross-transplantation studies have demonstrated that the kidney's genotype plays a role in determining the blood pressure of the recipient in Dahl S and R rats, the present experiments were designed to determine whether both blood pressure and urinary kallikrein excretion "traveled with the kidney" in transplantation. The Rapp strains of S and R were maintained on a low- NaCl (0.13%) diet until kidney transplantation (bilaterally nephrectomized recipients), at which time the diet was switched to high NaCl (7.8%). Sixteen days later, blood pressures (tail-cuff plethysmography) of the cross-transplant groups (R/S and S/R, indicating kidney genotype/recipient genotype) were nearly identical to each other and intermediate between the blood pressures of the control groups with transplanted kidneys (R/R and S/S). Renal function studies, performed on anesthetized rats 17 days after surgery, demonstrated that R kidneys had higher glomerular filtration rates, renal plasma flows, and urinary kallikrein excretion rates than S kidneys. These differences tended to be preserved in the cross-transplant groups, and therefore they must be genetically determined intrinsic differences between R and S kidneys. This was especially striking with respect to urinary kallikrein excretion. The rank order of urinary kallikrein excretion was R/R = R/S > S/R = S/S, which implies that it is completely determined by the genotype of the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Purinergic P2y receptors stimulate renin secretion by rat renal cortical slices.

These experiments were designed to characterize P2 purinergic receptor-mediated effects on renin secretion, using the rat renal cortical slice preparation. 2-Methylthio ATP (10-500 microM) and ATP (100-500 microM) stimulated renin secretion in a concentration-dependent manner and 2-methylthio ATP was the more potent. By contrast, alpha, beta-methylene ATP (0.1-500 microM) had no effect on renin secretion. This order of potency (2-methylthio ATP > ATP > alpha, beta-methylene ATP) indicates that activation of the P2y subclass of purinergic receptors stimulates renin secretion. Theophylline did not antagonize the effect of 2-methylthio ATP, which suggests that the effect was not due to a conversion of 2-methylthio ATP to 2-methylthio adenosine, followed by activation of P1 purinergic receptors. In contrast, N omega-nitro-I-arginine methyl ester both antagonized the basal renin secretory rate and blocked the stimulating effects on renin secretion of 2-methylthio ATP. Because N omega-nitro-l-arginine methyl ester antagonizes the production of nitric oxide by endothelial cells, these results suggest that nitric acid stimulates basal renin secretion in this experimental preparation and that increased production of it mediates the stimulating effects on renin secretion of activation of P2y purinergic receptors.

The effects of cyclosporine in Lewis rats with native and transplanted kidneys.

Several previous observations are consistent with the hypothesis that transplanted kidneys, because they are denervated, are protected from CsA-induced decreases in blood flow and glomerular filtration rate. The present experiments were designed to test this hypothesis, by using isogeneic Lewis rats as kidney donors and recipients. The recipients were unilaterally nephrectomized, such that each had one native and one transplanted kidney. Two to four weeks later, the insulin and PAH clearances of the two kidneys were measured and compared. CsA (10 mg kg-1 day-1) decreased inulin and PAH clearances, without affecting the PAH extraction. Thus, CsA decreased GFR and renal plasma flow. However, the decreases were not significantly different in native versus transplanted kidneys. Therefore, transplanted kidneys, at least in Lewis rats, are not protected from the adverse effects of CsA on renal hemodynamics.

Role of endothelium-derived nitric oxide in hemodynamic adaptations after graded renal mass reduction.

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)

Muscle metaboreflex control of vasopressin and renin release.

Dynamic exercise causes an increase in circulating blood levels of renin and vasopressin (AVP), yet the afferent mechanisms responsible for release of renin and AVP during exercise are poorly understood. Partial ischemia of active skeletal muscle induces a reflex pressor response, termed the muscle metaboreflex. Does muscle metaboreflex activation induce release of renin and AVP? The muscle metaboreflex was activated in conscious, chronically instrumented dogs during mild treadmill exercise (3.2 km/h, 0% grade) via graded partial occlusion of terminal aortic blood flow. Decreasing hindlimb perfusion to 40% of the control level during exercise significantly increased systemic arterial pressure (SAP) and heart rate (HR) from 103.4 +/- 2.4 to 166.7 +/- 4.2 mmHg and from 111.6 +/- 9.9 to 141.9 +/- 3.9 beats/min, respectively. However, only small nonsignificant changes in arterial plasma renin activity and AVP concentration occurred [control: renin = 0.46 +/- 0.8 ng angiotensin I (ANG I).ml-1.h-1, AVP = 0.53 +/- 0.17 pg/ml; metaboreflex activation: renin = 0.77 +/- 0.33 ng ANG I.ml-1.h-1, AVP = 1.09 +/- 0.34 pg/ml]. The experiments were repeated after ganglionic blockade (hexamethonium 10 mg/ml and atropine 0.2 mg/ml iv) to attenuate the reflex increase in SAP. In this setting, metaboreflex activation caused SAP to increase from 91.6 +/- 4.3 to only 114.7 +/- 6.8 mmHg and the reflex tachycardia was abolished (153.7 +/- 5.8 to 159.3 +/- 6.1 beats/min, P > 0.05). With the reflex pressor response markedly attenuated, AVP increased from 2.53 +/- 0.81 to 34.38 +/- 6.59 pg/ml with muscle metaboreflex activation, whereas no significant changes in renin activity occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological characterization of the renovascular P2 purinergic receptors.

Isolated rat kidneys, perfused at a constant flow with a nonrecirculated medium, were used to investigate the effects of P2 purinergic receptor agonists on renal vascular resistance. A potent P2y agonist, 2-methylthio ATP, dilated the kidney in a concentration-dependent manner, a response that was similar to that elicited by acetylcholine. The vasodilator responses to 2-methylthio ATP and to acetylcholine were nearly abolished by N omega-nitro-/-arginine methyl ester, an antagonist of nitric oxide formation by endothelial cells. A potent P2x agonist, alpha, beta-methylene ATP, constricted the kidney in a concentration-dependent manner, and the effect was potentiated by N omega-nitro-/-arginine methyl ester. This latter finding suggests that alpha,beta-methylene ATP activates P2y receptors, but with such a low potency that any tendency for vasodilation is masked by the predominant P2x receptor-induced constriction. Collectively, the results indicate the renal vasculature can either constrict or dilate in response to P2 purinergic receptor agonists, depending upon which subclass of receptor is activated, P2x (constrict) or P2y (dilate). Furthermore, the P2y receptor-induced vasodilation appears to be mediated by endothelial cell nitric oxide formation.

Reversible compensatory hypertrophy in rat kidneys: morphometric characterization.

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)

Prostaglandins do not mediate impaired autoregulation or increased renin secretion in remnant rat kidneys.

The rat remnant kidney model, produced by approximately five-sixths reduction in functional renal mass, is characterized by renal vasodilation, impaired autoregulation, and increased activity of the renin-angiotensin system. The present studies were designed to investigate the role of vasodilatory prostaglandins (PGs) in the altered hemodynamics in the remnant kidney. Four weeks post-ablation, renal blood flow (RBF), was significantly higher in rats fed a standard protein (SP) diet (n = 16) compared with low-protein-fed (LP) rats (n = 7) (6.2 +/- 0.6 vs. 3.7 +/- 0.5 ml/min; P < 0.01), autoregulation was impaired in SP rats [autoregulation index (AI) 1.0 +/- 0.1 (SP) vs. 0.2 +/- 0.1 (LP); P < 0.05], and renin secretory rates were significantly increased in SP rats both during the basal state [24 +/- 7 (SP) vs. 2 +/- 1 (LP) ng.ml-1 x h-1 x min-1; P < 0.05] and after reduction in renal perfusion pressure [110 +/- 29 (SP) vs. 16 +/- 7 (LP); P < 0.05]. Indomethacin administration (5 mg/kg bolus + 5 mg.kg-1 x h-1 infusion) in additional SP rats (n = 11) decreased RBF from 7.4 +/- 1.1 to 5.9 +/- 1.0 ml/min (P < 0.05) without improvement in autoregulation (AI = 1.1 +/- 0.3). Renin basal secretory rate and response to decreased renal perfusion pressure were not altered by indomethacin. These data suggest that PGs contribute to the renal vasodilation in the rat remnant kidney model, but they do not mediate the impaired renal autoregulation or the increased renin release.

Kidney cross transplants in Dahl salt-sensitive and salt-resistant rats.

Previous kidney cross-transplant studies have demonstrated that the genotype of the kidney plays a role in determining the blood pressure of the recipient in Dahl salt-sensitive (S) and salt-resistant (R) rats. The present studies were designed to elucidate this role. Kidney cross transplants were performed in unilaterally nephrectomized male recipients (John Rapp strains), such that each rat had a native kidney and a transplanted kidney of the opposite genotype. S and R rats with a native kidney and a transplanted kidney of the same genotype served as controls. After 4 wk on a 7.8% NaCl diet, rats were anesthetized and renal clearance studies were performed. S kidneys had lower glomerular filtration rate (GFR) and renal plasma flow (RPF) than R kidneys, and these differences were determined by the kidney's genotype rather than the recipient's, since S kidneys in R recipients tended to have lower GFR and RPF than R kidneys in S recipients. In contrast, independent of the kidney's genotype, the kidneys in S rats tended to have higher fractional excretion of H2O and Na (FEH2O and FENa) than the kidneys in R rats. Thus there were genetically determined differences in renal function between S and R rats; some (RPF and GFR) were intrinsic to the kidney, whereas others (FEH2O and FENa) were intrinsic to the host.(ABSTRACT TRUNCATED AT 250 WORDS)