Abstract
Objective:The Dahl salt-sensitive rat is a well-established model of salt-sensitive hypertension. The goal of this study was to assess the expression and activity of renal sodium channels and transporters in the renin-deficient salt-sensitive rat.Methods:Renin knockout (Ren−/−) rats created on the salt-sensitive rat background were used to investigate the role of renin in the regulation of ion transport in salt-sensitive hypertension. Western blotting and patch-clamp analyses were utilized to assess the expression level and activity of Na+ transporters.Results:It has been described previously that Ren−/− rats exhibit severe kidney underdevelopment, polyuria, and lower body weight and blood pressure compared to their wild-type littermates. Here we found that renin deficiency led to decreased expression of sodium-hydrogen antiporter (NHE3), the Na+/H+ exchanger involved in Na+ absorption in the proximal tubules, but did not affect the expression of Na-K-Cl cotransporter (NKCC2), the main transporter in the loop of Henle. In the distal nephron, the expression of sodium chloride cotransporter (NCC) was lower in Ren−/− rats. Single-channel patch clamp analysis detected decreased ENaC activity in Ren−/− rats which was mediated via changes in the channel open probability.Conclusion:These data illustrate that renin deficiency leads to significant dysregulation of ion transporters.
Highlights
The renin-angiotensin-aldosterone system (RAAS) is the central regulator of water and salt homeostasis in the body
Previous studies have shown that introgression of chromosome 13 (Chr 13) from the Brown Norway (BN) rat into the SS genetic background attenuates the development of hypertension in an SS-13BN consomic strain
Ren−/− rats were previously reported to differ from their Ren+/+ littermates by having significantly lower body weights and kidney underdevelopment marked by displaced medulla, incomplete formation of the medullary rays, and occurrence of large central lesions.[11]
Summary
The renin-angiotensin-aldosterone system (RAAS) is the central regulator of water and salt homeostasis in the body. Components of this hormonal cascade are major targets for pharmaceutical agents aimed at controlling blood pressure, and heart and kidney functions. Dahl salt-sensitive (SS) SS/JrHsdMcwi rats are extensively used to study the role of salt consumption in the development of hypertension. These rats, when kept on a high salt diet, exhibit remarkable phenotypic traits similar to those seen in the hypertensive African American population, including low renin, salt-sensitivity, hyperinsulinemia, and early end stage renal disease.[1,2,3]. While Chr 13 contains the renin gene, further studies, which narrowed the protective loci in the SS-13BN rats against salt-sensitivity, did not identify the renin gene in these regions.[4,5,6] a number of other studies demonstrated that genetic modification of the renin locus does affect blood pressure.[7,8,9,10]
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