Proximal Tubule‐Specific Transgenic Overexpression of Peroxisome Proliferator‐Activated Receptor Alpha Prevents the Development of Hypertension in Dahl Salt‐Sensitive Rats

Abstract

The Dahl salt‐sensitive rat (Dahl SS) is a well investigated model of hypertension that mimics human salt sensitive hypertension. These rats develop a significant increase in blood pressure and renal disease when challenged with a high salt diet compared to salt‐resistant strains. Prolonged high salt feeding results in extensive renal pathology, including glomerular and proximal tubular pathology, tubular casting, and interstitial fibrosis. It has been shown that clofibrate, a lipid lowering peroxisome proliferator‐activated receptor alpha (PPARα) agonist, can prevent the hypertensive phenotype in Dahl SS rats. PPARα is a ligand activated transcription factor that regulates β‐oxidation of fatty acids (FAO). The proximal tubule is a very metabolically active tubular segment that relies primarily on FAO to meet its high energy requirements. Reduced FAO can lead to proximal tubular damage and renal dysfunction. To investigate the impact of PPARα‐mediated FAO during a high‐salt challenge, we developed a novel transgenic Dahl SS strain with a proximal tubule‐specific promoter from the sodium/glucose cotransporter 2 gene (Sglt2). This resulted in the overexpression of Ppara only in the proximal tubule (SSTgPTPpara). At 9 weeks of age, male wild‐type rats and heterozygous transgenic SSTgPTPpara rats were placed on a 4.0% NaCl, high salt diet (n=6/group). Following a 14‐day high salt challenge, rats were anesthetized for carotid blood pressure recording. Proximal tubule‐specific transgenic overexpression of PPARα in heterozygous SSTgPTPpararats had lower systolic blood pressure when compared to wild‐type littermates (161.2.6 ± 12.0 mmHg vs.122.8 ± 4.2 mmHg; mean ± SEM; p <0.05, t‐test), as well as mean arterial pressure and diastolic blood pressure. Immunohistochemical analysis confirmed an increase in PPARA protein within proximal tubules of the renal cortex, relative to other nephron segments. In conclusion, proximal tubule specific‐transgenic overexpression of PPARα reduced salt‐sensitive hypertension, suggesting that proximal tubules may be one of the primary sites of anti‐hypertensive actions of clofibrate in Dahl SS rats. This also indicates that the SSTgPTPpara rat model could be useful for studying the contribution of dysregulated proximal tubule metabolism to salt‐sensitive hypertension and renal pathology in the Dahl SS rat.