Blood pressure and renal failure in the Fawn-Hooded rat: combining physiology and genetics

The question why not all patients with hypertension develop end-stage renal failure (ESRF) has become a major issue in nephrology and hypertension research over the past decade. There are indications for a relationship between hypertension and impaired renal fimction in individuals with no underlying renal disease.31 It is widely believed that genetic factors play an important role in the susceptibility to hypertension-induced renal failure.18.IOO Epidemiological studies indicate that the risk for hypertension-associated renal failure varies with the ethnic background. 14.28 For instance, the presence of ESRF in an AfricanAmerican individual results in a nine-fold increased risk of ESRF in a firstdegree relative, even after controlling hypertension in the relative.32 Most information on familial clustering of renal failure and hypertension is derived from studies in patients with diabetic nephropathy, for which Seaquist et al. recently showed the involvement of genetic factors in its pathogenesis. I08 Other studies have reported a greater prevalence of hype11ension and/or cardiovascular disease in the parents of children who developed diabetic nephropathy later in Iife.27 • 133 Furthermore, Schmidt et al. found that a familial history of hypertension is not only more frequent in patients who develop chronic renal failure caused by diabetes but also in patients with different histologic types of primary glomel1llonephritis. lo7 The factors responsible for an association between blood pressure and renal failure are not known, but an increased blood pressure is: (a) necessmy and sufficient to cause ESRF, or (b) necessmy but not sufficient to cause ESRF, or (c) neither nec~ssmy nor sufficient to cause ESRF; it accelerates the risk in individuals who are otherwise predisposed. Renal failure is hypertension-induced in the first two suppositions and hypertension-associated in the latter. 12 In this context, we have to consider the possibility that hypertension and the predisposition to develop glomel1llar damage due to hypertension are influenced by different genes. Gene-gene and gene-environment interactions determine the final phenotype. It could be that hype11ension alone and renal failure due to hypertension are two different phenotypes. The genetic basis of complications in human diseases deserves more attention, and it would be usefill to asce11ain a large number of hypertensive affected sibpairs to study whether risk of renal failure correlates between these sib-pairs and, if so, to map human susceptibility factors. Using the candidate gene approach, an insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene was recently discovered, significantly influencing circulating ACE levels. These levels might playa role in the development of target organ damage, such as left ventricular hYfelirophy in essential hypeliension and microalbuminuria in diabetes mellitus. I .29.83 However, simple comparisons do not provide answers to these complex problems. Combining physiology and genetics, we might be able to dissect the susceptibility to hypeliension and renal damage

Altered renal hemodynamics and impaired myogenic responses in the fawn-hooded rat

The present study examined whether an abnormality in the myogenic response of renal arterioles that impairs autoregulation of renal blood flow (RBF) and glomerular capillary pressure (PGC) contributes to the development of renal damage in fawn-hooded hypertensive (FHH) rats. Autoregulation of whole kidney, cortical, and medullary blood flow and PGC were compared in young (12 wk old) FHH and fawn-hooded low blood pressure (FHL) rats in volume-replete and volume-expanded conditions. Baseline RBF, cortical and medullary blood flow, and PGC were significantly greater in FHH than in FHL rats. Autoregulation of renal and cortical blood flow was significantly impaired in FHH rats compared with results obtained in FHL rats. Myogenically mediated autoregulation of PGC was significantly greater in FHL than in FHH rats. PGC rose from 46 +/- 1 to 71 +/- 2 mmHg in response to an increase in renal perfusion pressure from 100 to 150 mmHg in FHH rats, whereas it only increased from 39 +/- 2 to 53 +/- 1 mmHg in FHL rats. Isolated perfused renal interlobular arteries from FHL rats constricted by 10% in response to elevations in transmural pressure from 70 to 120 mmHg. In contrast, the diameter of vessels from FHH rats increased by 15%. These results indicate that the myogenic response of small renal arteries is altered in FHH rats, and this contributes to an impaired autoregulation of renal blood flow and elevations in PGC in this strain

Impaired autoregulation of renal blood flow in the fawn-hooded rat

The responses to changes in renal perfusion pressure (RPP) were compared in 12-wk-old fawn-hooded hypertensive (FHH), fawn-hooded low blood pressure (FHL), and August Copenhagen Irish (ACI) rats to determine whether autoregulation of renal blood flow (RBF) is altered in the FHH rat. Mean arterial pressure was significantly higher in conscious, chronically instrumented FHH rats than in FHL rats (121 +/- 4 vs. 109 +/- 6 mmHg). Baseline arterial pressures measured in ketamine-Inactin-anesthetized rats averaged 147 +/- 2 mmHg (n = 9) in FHH, 132 +/- 2 mmHg (n = 10) in FHL, and 123 +/- 4 mmHg (n = 9) in ACI rats. Baseline RBF was significantly higher in FHH than in FHL and ACI rats and averaged 9.6 +/- 0.7, 7.4 +/- 0.5, and 7.8 +/- 0.9 ml. min-1. g kidney wt-1, respectively. RBF was autoregulated in ACI and FHL but not in FHH rats. Autoregulatory indexes in the range of RPPs from 100 to 150 mmHg averaged 0.96 +/- 0.12 in FHH vs. 0.42 +/- 0.04 in FHL and 0.30 +/- 0.02 in ACI rats. Glomerular filtration rate was 20-30% higher in FHH than in FHL and ACI rats. Elevations in RPP from 100 to 150 mmHg increased urinary protein excretion in FHH rats from 27 +/- 2 to 87 +/- 3 microg/min, whereas it was not significantly altered in FHL or ACI rats. The percentage of glomeruli exhibiting histological evidence of injury was not significantly different in the three strains of rats. These results indicate that autoregulation of RBF is impaired in FHH rats before the development of glomerulosclerosis and suggest that an abnormality in the control of renal vascular resistance may contribute to the development of proteinuria and renal failure in this strain of rats

New rat model that phenotypically resembles autosomal recessive polycystic kidney disease

Numerous murine models of polycystic kidney disease (PKD) have been described. While mouse models are particularly well suited for investigating the molecular pathogenesis of PKD, rats are well established as an experimental model of renal physiologic processes. Han:SPRD-CY: rats have been proposed as a model for human autosomal dominant PKD. A new spontaneous rat mutation, designated wpk, has now been identified. In the mutants, the renal cystic phenotype resembles human autosomal recessive PKD (ARPKD). This study was designed to characterize the clinical and histopathologic features of wpk/wpk mutants and to map the wpk locus. Homozygous mutants developed nephromegaly, hypertension, proteinuria, impaired urine-concentrating capacity, and uremia, resulting in death at 4 wk of age. Early cysts were present in the nephrogenic zone at embryonic day 19. These were localized, by specific staining and electron microscopy, to differentiated proximal tubules, thick limbs, distal tubules, and collecting ducts. In later stages, the cysts were largely confined to collecting ducts. Although the renal histopathologic features are strikingly similar to those of human ARPKD, wpk/wpk mutants exhibited no evidence of biliary tract abnormalities. The wpk locus maps just proximal to the CY: locus on rat chromosome 5, and complementation studies demonstrated that these loci are not allelic. It is concluded that the clinical and renal histopathologic features of this new rat model strongly resemble those of human ARPKD. Although homology mapping indicates that rat wpk and human ARPKD involve distinct genes, this new rat mutation provides an excellent experimental model to study the molecular pathogenesis and renal pathophysiologic features of recessive PKD

Blood pressure and the susceptibility to renal damage after unilateral nephrectomy and L-NAME-induced hypertension in rats

BACKGROUND: Fawn-hooded hypertensive (FHH) rats carry several genes which determine the susceptibility to develop renal damage, while renal damage resistant August x Copenhagen Irish (ACI) rats do not. Kidneys from heterozygous (FHH x ACI) F(1) rats, appear to be largely, but not completely, protected after blood pressure elevation with N(omega)-nitro-L-arginine methyl ester (L-NAME). We examined the role of an increased haemodynamic burden on the development of renal damage combining unilateral nephrectomy (UNx)- and L-NAME-induced hypertension in F(1) and ACI rats. Additionally, we investigated whether a general toxic effect of L-NAME, independent from a blood pressure elevation, caused renal damage in F(1) rats in animals simultaneously treated with L-NAME and the ACE inhibitor lisinopril. METHODS: Surgery was performed and L-NAME treatment (50 or 150 mg/l) was started at the age of 15 weeks. Systolic blood pressure (SBP) and urinary albumin excretion (UaV) were measured at 6 and 12 weeks post-UNx, followed by autopsy to determine the incidence of focal glomerulosclerosis (FGS). Using lisinopril (LIS) and L-NAME, another group of rats was evaluated at 12, 18, and 24 weeks after start of treatment. RESULTS: At similar L-NAME intake, F, rats developed more severe hypertension and more UaV than ACI rats. The increase in UaV per mmHg increase in SBP was fivefold higher in F(1) compared with ACI rats. In F(1) rats, the increase in UaV per percentage incidence increase in FGS was three times higher. In LIS treated F(1) rats, no significant UaV or FGS was measured at low blood pressure levels, indicating that renal damage in hypertensive F(1) rats is not a direct effect of L-NAME, but the result of the high blood pressure or another action of the renin-angiotensin system. CONCLUSION: We conclude that heterozygosity for the genes influencing the development of renal damage in the FHH strain increases the susceptibility of the kidney to develop damage after UNx combined with systemic hypertension