Salt sensitive genotype is required for high fat diet associated hypertension and renal inflammation/injury in male Dahl rats
Authors: Xu Hui , Graver Hannah , Fernandes Roxanne , Jin Yining , Yarand Gloria , Harkema Jack R. , Rockwell Cheryl E. , Galligan James J. , Fink Gregory D. 
Published: April 2020

Elevated salt sensitivity and sympathetic activity are reported to contribute to obesity/high fat diet (HFD) associated hypertension and renal injury. We have reported that feeding male Dahl salt‐sensitive (SS) rats a HFD (with normal salt) robustly increases blood pressure and sympathetic support of blood pressure, and also causes severe renal inflammation/injury, when compared to male Dahl SS rats fed a standard rat diet (10% kcal from fat). However, it is hard to distinguish the effects of HFD per se on blood pressure and renal inflammation/injury in that setting, since Dahl SS rats fed a standard diet also develop moderate hypertension and mild renal inflammation/injury. To more clearly examine the effect of the SS genotype itself, in the current study we compared the impact of HFD on blood pressure and renal inflammation/injury in male SS (SS/JrHsd) and salt‐resistant (SR/JrHsd) rats (genetic control of SS rats) (Envigo). After 24 weeks on HFD diet feeding, starting at weaning (60% kcal from fat, 0.3% NaCl), SS rats developed severe hypertension (MAP 162±5mmHg, n=6) and renal inflammation/injury as expected. But SR rats on HFD had normal blood pressure (104±8mmHg, n=8) and renal histology. Compared with SS rats, SR rats showed much smaller mean arterial pressure (MAP) responses to acute ganglion blockade (hexamethonium, 30mg/kg, ip) (−14±5mmHg vs −37±5mmHg, P<0.05) and to chronic treatment with the angiotensin converting enzyme inhibitor enalapril (250mg/kg, 7 days in drinking water) (−21±7 mmHg vs −57±8 mmHg, P<0.05). SR rats showed less HFD associated metabolic disorders as they had lower body weight and plasma levels of cholesterol and triglycerides. SR rats also had much smaller spleen weights than SS rats. Immune cell analysis by flow‐cytometry showed that the splenic CD8+ population in SR rats was higher than that found in SS rats (16.4±0.7% vs 10.3±0.4%, P<0.05), whereas the CD4+ cell population was lower than that found in SS rats (18.3±0.6% vs 21.3±0.8%, P<0.05). The ratio of splenic CD4+/CD8+ was also significantly higher in SS rats than SR rats (2.10±0.08 vs 1.13±0.05, P<0.05). There were no strain differences in NK cells and B cells. Our study indicates that in male Dahl rats on HFD, the associated hypertension, metabolic disorders and renal inflammation/injury all require a salt sensitive genotype. Our study also confirms that the mechanisms responsible for HFD induced hypertension in male Dahl SS rats include increased neurogenic support of blood pressure and increased activity of the renin‐angiotensin system. Our study further suggests that a salt sensitive genotype impacts immune system responses to HFD. The mechanisms responsible for diet associated differences in immune cell regulation in the salt sensitive genetic background remain unknown.

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NHLBI 2P01HL070687 for G.D.F, J.J.G. and H.X