Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension

Pravenec, Michal; Churchill, Paul C.; Churchill, Monique C.; Viklický, Ondřej; Kazdová, Ludmila; Aitman, Timothy J.; Petretto, Enrico; Hübner, Norbert; Wallace, Caroline A.; Zimdahl, Heike; Zidek, Vaclav; Landa, V.; Dunbar, Joseph C.; Bidani, A.; Griffin, Karen A.; Qi, Nathan; Maxová, Martina; Křen, Vladimı́r; Mlejnek, Petr; Wang, Jiaming; Kurtz, Theodore W.

doi:10.1038/ng.164

Cited by 97 publications

(78 citation statements)

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“…Just as CD36 was downregulated in the renal cortex here, Cd36 is downregulated in spontaneously hypertensive rat kidney and predisposes this strain to hypertension. 25 miRNAs have been implicated in cardiovascular disease, 26 cancer, 27 and, for one (miR-155), hypertension, where miR-155 targets a hypertension-associated SNP (rs5186) in the angiotensin II type 1 receptor 3ЈUTR. 28,29 Elevated angiotensin II type 1 receptor in young hypertensives homozygous for the rs5186 C allele tracks positively with BP and negatively with hsa-miR-155 expression.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling Reveals Renin mRNA Overexpression in Human Hypertensive Kidneys and a Role for MicroRNAs

et al. 2011

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Abstract-The kidney has long been invoked in the etiology of essential hypertension. This could involve alterations in expression of specific genes and microRNAs (miRNAs). The aim of the present study was to identify, at the transcriptome-wide level, mRNAs and miRNAs that were differentially expressed between kidneys of 15 untreated hypertensive and 7 normotensive white male subjects of white European ancestry. By microarray technology we found 14 genes and 11 miRNAs that were differentially expressed in the medulla. We then selected and confirmed by real-time quantitative PCR expression differences for NR4A1, NR4A2, NR4A3, PER1, and SIK1 mRNAs and for the miRNAs hsa-miR-638 and hsa-let-7c. Luciferase reporter gene experiments in human kidney (HEK293) cells confirmed the predicted binding of hsa-let-7c to the 3Ј untranslated region of NR4A2 mRNA. In the renal cortex we found differential expression of 46 genes and 13 miRNAs. We then confirmed expression differences for AIFM1, AMBP, APOE, CD36, EFNB1, NDUFAF1, PRDX5, REN, RENBP, SLC13A1, STX4,. Functional experiments in HEK293 cells demonstrated that hsa-miR-663 can bind to the REN and APOE 3Ј untranslated regions and can regulate REN and APOE mRNA levels, whereas hsa-miR-181a regulated REN and AIFM1 mRNA. Our data demonstrated for the first time that miRNAs can regulate renin expression. The observed downregulation of 2 miRNAs in hypertension could explain the elevation in intrarenal renin mRNA. Renin, CD36, and other mRNAs, as well as miRNAs and associated pathways identified in the present study, provide novel insights into hypertension etiology. (Hypertension. 2011;58:1093-1098.) • Online Data SupplementKey Words: microarrays Ⅲ microRNAs Ⅲ renin angiotensin system Ⅲ kidney Ⅲ hypertension S olving the molecular etiology of essential hypertension has been challenging. 1 Studies of selected blood pressure (BP) genes and large genome-wide association studies have identified only a handful of gene variants of small effect sizes. The interplay between genetic and environmental factors that contributes to the heterogeneity of hypertension has made the identification of causative alleles, genes, and transcripts difficult. 1 A further impediment has been the difficulty in obtaining suitable human tissue samples other than blood.Guyton and colleagues 2,3 theorized that hypertension is caused by a primary defect in the kidney. This idea has gained support from rare monogenic forms of hypertension, in which single mutations in genes responsible for renal sodium reabsorption 4 result in BP elevation. 3 MicroRNAs (miRNAs) are important for physiological and pathophysiological processes in various diseases. 5 These 18 to 30 nucleotides noncoding RNAs regulate the expression and translation of half of protein-coding mRNAs in humans by binding to target sites in the 3Ј untranslated region (UTR) to destabilize them or impede translation. 5 If miRNAs modulate mRNAs for BP genes, they could form the basis for novel antihypertensive therapies. 6,7 Knowledge of effects of miRNAs ...

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Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling Reveals Renin mRNA Overexpression in Human Hypertensive Kidneys and a Role for MicroRNAs

et al. 2011

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“…39 Aitman et al 39 showed that an SHR/NIH derived strain had a deletion of Cd36 located in a QTL region, suggesting that this gene was contributing to insulin resistance in this strain. Using transgenic rescue studies, Pravenec et al 40,41 definitively demonstrated that genetic deficiency in the expression of Cd36 can contribute to both insulin resistance and increased BP in rats derived from the SHR/NIH strain. In the following studies on rats and humans, substantial evidence was accumulated supporting the role of Cd36 in hypertension and insulin resistance.…”

Section: Systematic Gene Expression Analysis: Cd36mentioning

confidence: 99%

The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

et al. 2012

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The stroke-prone spontaneously hypertensive rat (SHRSP) is a unique genetic model of severe hypertension and cerebral stroke. SHRSP, as well as the spontaneously hypertensive rat, the parental strain of SHRSP, has made a tremendous contribution to cardiovascular research. However, the genetic mechanisms underlying hypertension and stroke in these rats have not yet been clarified. Recent studies using whole-genome sequencing and comprehensive gene expression analyses combined with classical quantitative trait loci analyses provided several candidate genes, such as Ephx2, Gstm1 and Slc34a1, which still need further evidence to define their pathological roles. Currently, genome-wide association studies can directly identify candidate genes for hypertension in the human genome. Thus, genetic studies in SHRSP and other rat models must be focused on the pathogenetic roles of 'networks of interacting genes' in hypertension, instead of searching for individual candidate genes. Keywords: cerebral stroke; genetics; hypertension; QTL; SHRSP INTRODUCTIONThe stroke-prone spontaneously hypertensive rat (SHRSP) is a unique genetic model of severe hypertension and cerebral stroke. Two decades have passed since the first pioneering studies on quantitative trait loci (QTLs) of blood pressure (BP) in SHRSP. 1,2 In spite of all efforts, the genetic mechanisms underlying hypertension or cerebral stroke in this rat model remain unknown. During this period, genetic analyses in humans have progressed dramatically. Technologies have made it possible to genotype a large number of samples and analyze an enormous amount of single-nucleotide polymorphism data. Genome-wide association studies (GWAS) that rely on such advanced technologies have revealed a number of loci associated with increased BP in humans. [3][4][5][6][7][8][9][10] Under such circumstance, what is the role of SHRSP and other models in genetic studies of cardiovascular diseases? In this review, we will address this issue and summarize the genetic studies performed thus far in SHRSP.

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“…Indeed, its role has been well documented in the pathogenesis of diabetes and hypertension that are the leading causes of renal failure (10,11,15), but also atherosclerosis, inflammation, and lipid metabolism (16,17). A case-control study conducted on metabolic syndrome patients in Egypt showed that CD36 rs1761667 SNP is positively associated with increased risk of metabolic syndrome and its components (higher systolic blood pressure, wider waist circumstance, and higher degree of dyslipidemia) (17).…”

Section: Discussionmentioning

confidence: 99%

CD36 Gene Polymorphism and Susceptibility to Nephropathies

Houssaini¹

2015

IJIRSET

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Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension

Cited by 97 publications

References 14 publications

Gene Expression Profiling Reveals Renin mRNA Overexpression in Human Hypertensive Kidneys and a Role for MicroRNAs

Gene Expression Profiling Reveals Renin mRNA Overexpression in Human Hypertensive Kidneys and a Role for MicroRNAs

The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

CD36 Gene Polymorphism and Susceptibility to Nephropathies

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