Increased Renal Epithelial Na Channel Expression and Activity Correlate With Elevation of Blood Pressure in Spontaneously Hypertensive Rats

Abstract

N umerous quantitative trait loci for blood pressure (BP) elevation have been identified in essential hypertension in the last decade, followed by genome-wide association studies. [1][2][3][4][5] The high heritability of gene expression variation indicates that it may serve as an intermediate phenotype for the identification of genomic determinants of complex traits, such as essential hypertension. We initiated this approach by exploring the pleiotropic regulation of heat stress genes mapping the mRNA accumulation after heat stress and using recombinant inbred strains (RIS) developed by inbreeding the F 2 generation of normotensive Brown-Norway (BN-Lx) and spontaneously hypertensive rats (SHR). 6 We discovered a common regulator of heat stress genes, the rat heat stress transcription factor. 7 Subsequently, Hubner et al 8 undertook integrated gene expression profiling in the adipose tissue and kidneys of 6-week-old male animals from the same RIS. Dmitrieva et al 9 adopted this strategy for comparative analysis of common differentially-expressed genes in the kidneys of 4-, 8-, 12-, and 18-week-old males of 3 distinct SHR lines versus normotensive Wistar-Kyoto (WKY) rats. The renal transcriptomes of 2-week-old SHR and WKY females 10 and 9-week-old rats of both sexes 11 were compared by other research teams. However, results generated by these studies cannot serve to identify genes involved in the age-dependent development of hypertension. In the present investigation, we compared whole genome expression profiles in kidneys isolated from 12-, 40-, and 80-week-old male and female SHR and 4 RIS (HXB3, 13, 17, and 23) with different temporal patterns of hypertension development. Among the genes significantly correlating with increasing mean systolic and diastolic blood pressures, we noted the augmented mRNAs levels of Scnn1b and Scnn1g genes encoding β-and γ-epithelial Na channel (ENaC) subunits. The present study is thus focusing on the expression and activity of these genes in relation to age-dependent increase of blood pressure.Abstract-Elevation of blood pressure with age is one of the hallmarks of hypertension in both males and females. This study examined transcriptomic profiles in the kidney of 12-, 40-, and 80-week-old spontaneously hypertensive rats and 4 recombinant inbred strains in search for functional genetic elements supporting temporal dynamics of blood pressure elevation. We found that both in males and females of spontaneously hypertensive rats and hypertensive recombinant inbred strains age-dependent blood pressure increment was accompanied by 50% heightened expression of epithelial sodium channel β-and γ-subunits. Epithelial sodium channel subunit expression correlated positively with blood pressure but correlated negatively with renin expression. Increased epithelial sodium channel activity was observed in cultured epithelial cells isolated from the kidney medulla of 80-week-old spontaneously hypertensive rats but not in agematched normotensive Wistar Kyoto. This difference remained evident after ...

High Salt Diet Affects Renal Sodium Excretion and ERRα Expression

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Brown Norway Chromosome 1 Congenic Reduces Symptoms of Renal Disease in Fatty Zucker Rats

“…Rat chromosome 1 has several known renal disease genes (VPS10 domain receptor protein (Sorcs1 [9]), and Ras-related protein (Rab38 [8])), at least one gene that has been identified as a renal function gene in human genome wide association studies (Pancreatic secretory granule membrane major glycoprotein (Umod, [21]), orthologs of genes known to cause renal disease (Polycystic kidney disease 2-like 1 protein (Pkd2l1 [22])), and other genes that could plausibly influence renal disease (Aminopeptidase N precursor (Anpep [23]), Fumarylacetoacetase (Fah [24]), Aquaporin-11 (Aqp11 [25]), and Amiloride-sensitive sodium channel subunit gamma (Scnn1g [26]). Since we have previously demonstrated two QTL peaks for the albumin to creatinine ratio (ACR) in the BN donor region, one of which is quite broad, then there are at least two and probably more ACR genes in our congenic.…”

Mechanisms responsible for postmenopausal hypertension in a rat model: Roles of the renal sympathetic nervous system and the renin-angiotensin system

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