Effect of high NaCl diet on spontaneous hypertension in a genetic rat model with reduced nephron number

Kreutz, Reinhold; Kovačević, Larisa; Schulz, Angela; Rothermund, Lars; Ketteler, Markus; Paul, Martin

doi:10.1097/00004872-200018060-00017

Cited by 62 publications

(73 citation statements)

References 10 publications

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“…Our colony has been established in generation F 45 in 1996 by further inbreeding of rats obtained from the original colony (MWF/Ztm) (12). The genetic homogeneity of our MWF Fub colony was recently confirmed (6). Lew srats were obtained from M&B, Bomholtvej, Denmark, and a colony of Lew Fub rats was also established at our facility.…”

Section: Animalsmentioning

confidence: 76%

“…Most importantly, the ability to produce specific intercrosses between strains with low and high UAE rates represents a powerful experimental tool for carrying out genetic linkage analyses. The Munich Wistar Frömter (MWF) rat represents such an inbred genetic animal model that spontaneously develops an increased UAE (6). MWF animals develop also moderate spontaneous hypertension and exhibit a lower number of nephrons compared with other rat strains (7).…”

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confidence: 99%

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Genetic Dissection of Increased Urinary Albumin Excretion in the Munich Wistar Fro[Combining Diaeresis]mter Rat

Schulz

Litfin²,

Koßmehl³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. An elevated urinary albumin excretion (UAE) is a risk factor for the development of chronic nephropathy and for cardiovascular mortality. The Munich Wistar Frömter (MWF) rat represents a genetic model that develops spontaneously mild hypertension and a 142-fold increased UAE compared with normal Lewis rats at 14 wk of age. The genetic basis of UAE in male MWF was analyzed in relation to BP by using a quantitative trait (QTL) mapping strategy. F1-hybrids generated from a cross between MWF and Lewis rats showed normal UAE rates similar to Lewis. A backcross strategy including 213 animals was therefore used. To account for age-of-onset effects, UAE was determined in young backcross animals at 8 wk and in adult animals at 14 and 24 wk of age, respectively. Total genome scan analysis identified three QTL with significant linkage to UAE and one QTL with suggestive linkage to UAE. These loci showed no linkage to BP, and BP explained only 2% of the total variance of UAE. Homozygosity for the MWF allele accounted for a similar mean increase in UAE in adult backcross animals at each UAE QTL. When single gene effects were analyzed, only one UAE QTL led to a significant increase in UAE. Early onset of albuminuria and a considerable increase of UAE in adult animals required homozygosity at three loci at least. This study demonstrates the polygenetic recessive determination of increased UAE by a set of genes that are unlinked to BP.An elevated urinary albumin excretion (UAE) is a predictor of the development of nephropathy (1), and a moderate increase of UAE in the range of microalbuminuria represents an independent risk factor for cardiovascular events in patients with hypertension, diabetes or preexisting cardiovascular disease (2,3). With regard to the latter it is important to point out that microalbuminuria represents a quantitative clinical phenotype such as hypertension, which is arbitrarily defined on the basis of a quantitative cut-off value (1,4). Animal strains that display an increased UAE as an inherited trait represent an attractive substitute for the dissection of the polygenetic basis of UAE. Fully inbred animal models expressing a genetically determined disease avoid the problem of genetic heterogeneity, which in humans reduces statistical power to a degree that may preclude detection of individual genetic factors (5). In addition, animal experimentation allows a much more precise control of environmental factors compared with clinical studies. Most importantly, the ability to produce specific intercrosses between strains with low and high UAE rates represents a powerful experimental tool for carrying out genetic linkage analyses. The Munich Wistar Frömter (MWF) rat represents such an inbred genetic animal model that spontaneously develops an increased UAE (6). MWF animals develop also moderate spontaneous hypertension and exhibit a lower number of nephrons compared with other rat strains (7). Although both male and female MWF animals demonstrate a similar reduction in nephron number when compared w...

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Section: Animalsmentioning

confidence: 76%

mentioning

confidence: 99%

Genetic Dissection of Increased Urinary Albumin Excretion in the Munich Wistar Fro[Combining Diaeresis]mter Rat

Schulz

Litfin²,

Koßmehl³

et al. 2002

Journal of the American Society of Nephrology

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“…Systolic blood pressure and urinary albumin excretion were determined as previously reported. 12 Animals were killed under Ketamin HCl (87 mg kg À1 body weight; Ketanest S, Pfizer, Karlsruhe, Germany) and Xylazine (13 mg kg À1 body weight; Rompun, Beyer, Leverkusen, Germany) anesthesia at 14 weeks of age. After induction of anesthesia, the abdomen was opened by a vertical incision.…”

Section: Methods Animalsmentioning

confidence: 99%

Renal ACE2 expression and activity is unaltered during established hypertension in adult SHRSP and TGR(mREN2)27

et al. 2009

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Differential renal expression of a homolog of the angiotensin-converting enzyme (ACE), that is, ACE2, has been implicated as a genetic basis of polygenetic hypertension in the stroke-prone spontaneously hypertensive rat model. However, data on the role of ACE2 in hypertension are still inconclusive. Therefore, we analyzed kidney ACE2 mRNA, ACE2 protein and ACE2 enzyme activities in the adult polygenetic stroke-prone spontaneously hypertensive rat (SHRSP) and the monogenetic TGR(mREN2)27 rat models, in comparison with their normotensive reference strains, Wistar-Kyoto (WKY) and Spraque-Dawley (SD) rats, respectively. Kidney ACE2 mRNA was studied using quantitative real-time reverse transcriptase-PCR (RT-PCR) in cortex and medulla, whereas protein expression was scored semiquantitatively in detail in different renal structures using immunohistochemistry. Furthermore, total renal tissue ACE2 activity was measured using a fluorimetric assay that was specified by the ACE2 inhibitor DX600. In SHRSP and homozygous TGR(mREN2)27 rats with established hypertension, kidney ACE2 mRNA, protein and tissue ACE2 activities were not different from their respective WKY and SD reference strain, respectively. In addition, when we looked at renal localization, we found ACE2 protein to be predominantly present in glomeruli and endothelium with weak staining in distal and negative staining in proximal tubuli. Thus, our data challenge previous work that implicates ACE2 as a candidate gene for hypertension in SHRSP by reporting a significant reduction of ACE2 in the kidneys of SHRSP. Taken together, renal ACE2 is not altered in the SHRSP and TGR(mREN2)27 genetic rat models with established hypertension.

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“…Systolic blood pressure was measured in awake animals by the tail-cuff method as previously reported. 24 Details appear in the Supplementary Material online.…”

Section: Parameters Of Metabolic Syndromementioning

confidence: 99%

Microangiopathy and visual deficits characterize the retinopathy of a spontaneously hypertensive rat model with type 2 diabetes and metabolic syndrome

et al. 2010

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Retinopathy has been increasing in prevalence as a consequence of type 2 diabetes and a cluster of coexisting risk factors characterized as the metabolic syndrome. However, the combined effects of these conditions on the retina are poorly understood. Therefore, we focused on the spontaneously hypertensive corpulent rat (SHR/N-cp), a model with type 2 diabetes, obesity and features of the metabolic syndrome to characterize retinal changes at a structural and functional level. SHR/N-cp males at 4 and 8 months of age were used in this study. Metabolic parameters and blood pressure were measured by standard methods. Morphology was investigated by histological techniques supplemented by nicotinamide adenine dinucleotide phosphate-diaphorase staining of whole mounts and fluorescein angiography to analyze the retinal vasculature. The in vivo function of the retina was examined by electroretinography (ERG). Obese SHR/N-cp rats were hypertensive and showed significant increases in body weight, serum levels of glucose, triglycerides, total cholesterol and urinary glucose excretion compared with lean controls (Po0.01 for each). Histology indicated an overall intact integrity of the retina and aspects of microangiopathy in obese SHR/N-cp rats. ERG revealed intact processing of light signals but significantly decreased amplitudes of b-waves for all (Po0.01) and of a-waves for some examined light intensities (Po0.05). Oscillatory potentials were significantly protracted (Po0.01), whereas amplitudes were not reduced. Microangiopathy and electroretinographic deficits combine to produce an early non-proliferative retinopathy phenotype in the obese SHR/N-cp rats. Thus, this model represents a valuable experimental tool to obtain further insights into the mechanisms of retinopathy in the context of obesity, type 2 diabetes and metabolic syndrome.

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Effect of high NaCl diet on spontaneous hypertension in a genetic rat model with reduced nephron number

Abstract: Our findings demonstrate that both the hypertension and UAE are sensitive to high NaCl loading in female and male MWF/Fub rats. Thus, an inborn nephron deficit may lead to salt-sensitive hypertension and renal dysfunction.

Cited by 62 publications

References 10 publications

Genetic Dissection of Increased Urinary Albumin Excretion in the Munich Wistar Fro[Combining Diaeresis]mter Rat

Genetic Dissection of Increased Urinary Albumin Excretion in the Munich Wistar Fro[Combining Diaeresis]mter Rat

Renal ACE2 expression and activity is unaltered during established hypertension in adult SHRSP and TGR(mREN2)27

Microangiopathy and visual deficits characterize the retinopathy of a spontaneously hypertensive rat model with type 2 diabetes and metabolic syndrome

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