Salt Loading Promotes Kidney Injury via Fibrosis in Young Female Ren2 Rats

Abstract

Background/Aims: It is increasingly recognized that there is sexual dimorphism in kidney disease progression; however, this disparity is lost in the presence of diabetes where women progress at a similar rate to men. The renin-angiotensin-aldosterone system (RAAS) is known to regulate diabetes-induced kidney injury, and recent literature would suggest that gender differences exist in RAAS-dependent responses in the kidney. In this regard, these gender differences may be overcome by excessive salt intake. Thereby, we hypothesized that salt would promote proteinuria in transgenic female rats under conditions of excess tissue angiotensin (Ang) II and circulating aldosterone. Materials and Methods: We utilized young female transgenic (mRen2)27 (Ren2) rats and Sprague-Dawley (SD) littermates and fed a high-salt diet (4%) over 3 weeks. Results: Compared to SD and Ren2 controls, female Ren2 rats fed a high-salt diet displayed increases in proteinuria, periarterial and interstitial fibrosis as well as ultrastructural evidence of basement membrane thickening, loss of mitochondrial elongation, mitochondrial fragmentation and attenuation of basilar canalicular infoldings. These findings occurred temporally with increases in transforming growth factor-β but not indices of oxidant stress. Conclusions: Our current data suggest that a diet high in salt promotes progressive kidney injury as measured by proteinuria and fibrosis associated with transforming growth factor-β under conditions of excess tissue Ang II and circulating aldosterone.

Dietary Sodium Restriction Reduces Arterial Stiffness, Vascular TGF-β-Dependent Fibrosis and Marinobufagenin in Young Normotensive Rats

“…Notably, no significant changes in collagen deposition were observed in the renal cortex or medulla, and only a tendency for collagen increase around the small renal blood vessels was found in the cortex of the animals on an HS intake. Previous publications have documented an increase in the renal fibrosis in rats on an HS intake; the difference between our present study’s experimental setting and the settings in these publications are in the dietary salt amount (8% vs. 4% in our study) [ 30 , 36 , 41 ], or in the gender of the studied animals (females vs. males in the present study) [ 42 ].…”

Obesity and kidney disease: from population to basic science and the search for new therapeutic targets

“…115,116 There is considerable evidence that increased aldosterone signaling through MRs has an important role in the pathogenesis of tubulointerstitial fibrosis and progression of diabetic kidney disease. For example, aldosterone increases renal TGF-b and PAI-1 levels 117,118 (Figures 2 and 3). Further, blockade of MR activation attenuates tubulointerstitial fibrosis in a number of animal models.…”

The Role of Transforming Growth Factor β1 in the Regulation of Blood Pressure

“…In Sprague-Dawley rats receiving angiotensin II (100 ng/kg/min) for two weeks by subcutaneous minipump, a high sodium diet aggravated renal histological changes and the expression of TGFβ1 in the kidney without changing blood pressure [186]. Likewise, in young female transgenic (mRen2)27 rats a high-sodium diet for 3 weeks did not significantly alter blood pressure, but did exacerbate cardiac left ventricular diastolic dysfunction, proteinuria, periarterial and interstitial fibrosis; TGFβ1 expression in the kidney was increased as well [187, 188]. The same study found that salt loading increased fibrosis and TGFβ1 expression in the kidney even in normotensive Sprague-Dawley rats [187].…”