Genetic analysis of salt-sensitive hypertension in Dahl rats reveals a link between cardiac fibrosis and high cholesterol

Wendt, Norbert; Schulz, Angela; Qadri, Fatimunnisa; Bolbrinker, Juliane; Koßmehl, Peter; Winkler, Karl; Stoll, Monika; Vetter, Roland; Kreutz, Reinhold

doi:10.1093/cvr/cvn263

Cited by 17 publications

(11 citation statements)

References 41 publications

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“…In this study, we demonstrated that feeding mice with an HFCD for 6 weeks resulted in a 25% increase in their body weight, which is consistent with the findings of previous reports (Matsuzawa et al, 2007). An HFCD has been used to investigate the metabolic syndrome, including atherosclerosis, hypertension, and diabetes, in various mammals (Miriyala et al, 2006;Osto et al, 2008;Wendt et al, 2009;Wu et al, 2006). In wild-type or genetically modified animals, an HFCD induces a dramatic increase in the body weight, hepatomegaly, splenomegaly, high blood pressure, and an increase in the plasma lipid content.…”

Section: Discussionsupporting

confidence: 90%

Murine Hepatic miRNAs Expression and Regulation of Gene Expression in Diet-Induced Obese Mice

Park

Ahn

Kim

et al. 2011

Molecules and Cells

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MicroRNAs are short, non-coding RNA molecules that regulate gene expression primarily by translational repression or by messenger RNA degradation. MicroRNAs play crucial roles in various biological processes. However, little is known regarding their role in obesity. We investigated differences of microRNA (miRNA) expression in liver tissue from diet-induced obese mice and potential effects of them on gene and protein expression. We used a miRNA microarray and quantitative RT-PCR to determine miRNA expression in murine liver tissue. Gene and protein expression were determined by qRT-PCR and Western blot analysis. Effects of miRNA by knock-down using RNAi or overexpression on putative target genes and/or proteins in a murine hepatic cell line were also investigated. MicroRNA array and qRT-PCR analsysis revealed that > 50 miRNAs were down- or upregulated more than 2-fold in the liver of diet-induced obese mice. While changes in expression of many genes were observed at the mRNA level, some were only altered at the protein level. Overexpression or knock-down of miR-107 in murine hepatic cells revealed that the expression of its putative target, fatty acid synthase, was dramatically decreased or increased, respectively. In conclusion, more than 50 hepatic miRNAs were dysregulated in diet-induced obese mice. Some of them regulate protein expression at translation level and others regulate mRNA expression at transcriptional level. MiR-107 is downregulated while FASN, a putative target of miR-107, was increased in diet-induced obese mice. These findings provide the evidence of the correlation of miRNAs and their targets in diet-induced obese mice.

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Section: Discussionsupporting

confidence: 90%

Murine Hepatic miRNAs Expression and Regulation of Gene Expression in Diet-Induced Obese Mice

Park

Ahn

Kim

et al. 2011

Molecules and Cells

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“…Wendt et al . suggested a link between hypercholesterolemia and left ventricular fibrosis in Dahl salt-sensitive rats, which are genetically modulated by chromosome 19 28.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Stress Exacerbates the Progression of Cardiac Fibrosis in High-Fat-Fed Apolipoprotein E Knockout Mice via Endothelial-Mesenchymal Transition

Ling¹,

Liu²,

Ni³

et al. 2013

Int. J. Med. Sci.

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Background Chronic inflammation plays a crucial role in the progression of cardiac fibrosis. This study investigated whether inflammation exacerbated the progression of cardiac fibrosis in high-fat-fed apolipoprotein E knockout (ApoE KO) mice via endothelial-mesenchymal transition (EndMT).Methods Twenty-four male ApoE KO mice were divided into normal chow diet (Control), high-fat diet (HFD), or high-fat diet plus 10% casein injection (inflamed) groups for 8 weeks. The body weight of ApoE KO mice was measured at each week. The lipid profile and serum amyloid A (SAA) levels were examined using clinical biochemistry and enzyme-linked immunosorbent assays, respectively. Cardiac lipid and collagen accumulation was visualised with haematoxylin-eosin (HE) and Masson's trichrome staining. EndMT-related molecule expression was examined by immunohistochemistry and Western blotting.Results SAA levels were increased in the inflamed group compared with the HFD and control groups, suggesting that inflammation was successfully induced. There were no differences in body weight among three groups at each week. Interestingly, inflammation significantly reduced serum total cholesterol, triglyceride, and low-density lipoprotein (LDL) levels compared with the HFD mice. However, both foam cell formation in cardiac blood vessels and cardiac collagen deposition were increased in the inflamed group, as demonstrated by HE and Masson trichrome staining. Furthermore, inflammation reduced protein expression of CD31 and increased protein expression of alpha-smooth muscle actin (α-SMA) and collagen I, which contribute to cardiac EndMT.Conclusions Inflammatory stress exacerbates the progression of cardiac fibrosis in high-fat-fed ApoE KO mice via EndMT, suggesting that hyperlipidaemia and inflammation act synergistically to redistribute plasma lipids to cardiac tissues and accelerate the progression of cardiac fibrosis.

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“…16,38,43,48,53,54 The magnitude of albuminuria is not only enhanced by high-salt intake but also modified by the composition of dietary protein intake. 55,56 In addition, the rats develop left ventricular hypertrophy and fibrosis, 47,49,51,57 hyperlipidemia 46,51 and insulin resistance. [58][59][60] Cosegregation and linkage analyses Different studies addressed the genetics of albuminuria in SS rats under either normal/low-salt or high-salt diet.…”

Section: Dahl Rat Strain Breedingmentioning

confidence: 99%

Mapping genetic determinants of kidney damage in rat models

Schulz

Kreutz

2012

Hypertens Res

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During the last two decades, significant progress in our understanding of the development of kidney diseases has been achieved by unravelling the mechanisms underlying rare familial forms of human kidney diseases. Due to the genetic heterogeneity in human populations and the complex multifactorial pathogenesis of the disease phenotypes, the dissection of the genetic basis of common chronic kidney diseases (CKD) remains a difficult task. In this regard, several inbred rat models provide valuable complementary tools to uncover the genetic basis of complex renal disease phenotypes that are related to common forms of CKD. In this review, data obtained in nine experimental rat models, including the Buffalo (BUF), Dahl salt-sensitive (SS), Fawn-hooded hypertensive (FHH), Goto-Kakizaki (GK), Lyon hypertensive (LH), Munich Wistar Frömter (MWF), Sabra hypertension-prone (SBH), spontaneously hypertensive rat (SHR) and stroke-prone spontaneously hypertensive rat (SHRSP) inbred strains, that contributed to the genetic dissection of renal disease phenotypes are presented. In this panel of inbred strains, a large number of quantitative trait loci (QTL) linked to albuminuria/proteinuria and other functional or structural kidney abnormalities could be identified by QTL mapping analysis and follow-up studies including consomic and congenic rat lines. The comprehensive exploitation of the genotype-renal phenotype associations that are inherited in this panel of rat strains is suitable for making a significant contribution to the development of an integrated approach to the systems genetics of common CKD. INTRODUCTIONCommon forms of chronic kidney diseases (CKD) represent complex disease phenotypes that are influenced by both environmental and genetic factors. [1][2][3][4][5] Both arterial hypertension and type-2 diabetes mellitus are major contributors to complex CKD, which has a high prevalence in the general human population worldwide affecting B11-15% of individuals in Europe and United States. 6-9 CKD represents as expected a major risk factor for the progression to end-stage renal disease but associates also with an increased risk of cardiovascular morbidity and mortality. 10,11 In addition to the assessment of impaired renal function or glomerular filtration rate, urinary albumin excretion rate (albuminuria) represents another important clinical marker for the evaluation of CKD and cardiovascular risk of patients. [10][11][12][13][14][15] These renal disease phenotypes are also inherited in several inbred rat strains many of which are hypertensive. 16 During the last decades, genetic mapping studies by genome-wide linkage analysis followed by fine mapping of selected quantitative trait loci (QTL) for renal disease phenotypes were reported. Subsequently, studies in consomic and congenic rats were performed to further unravel the genetics of kidney injury in inbred rat strains. For QTL confirmation, consomic strains were generated by transfer of an entire chromosome carrying a QTL from a donor strain into the disease backgro...

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Genetic analysis of salt-sensitive hypertension in Dahl rats reveals a link between cardiac fibrosis and high cholesterol

Abstract: Our findings point to a link between hypercholesterolemia and LV fibrosis in salt-sensitive hypertension of SS rats which is genetically modulated by RNO19.

Cited by 17 publications

References 41 publications

Murine Hepatic miRNAs Expression and Regulation of Gene Expression in Diet-Induced Obese Mice

Murine Hepatic miRNAs Expression and Regulation of Gene Expression in Diet-Induced Obese Mice

Inflammatory Stress Exacerbates the Progression of Cardiac Fibrosis in High-Fat-Fed Apolipoprotein E Knockout Mice via Endothelial-Mesenchymal Transition

Mapping genetic determinants of kidney damage in rat models

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