Sex differences in renal inflammation and injury in high fat diet induced hypertension in Dahl salt sensitive rats
Authors: Fernandes Roxanne , Garver Hannah , Harkema Jack J. , Galligan James J. , Fink Gregory D. , Xu Hui 
Published: June 2021

The progression of hypertension and renal failure are normally faster in males than females. Renal inflammation is a common feature of experimental and clinical salt sensitive hypertension. The role of renal inflammation in high fat (HF) diet associated hypertension and renal injury has been studied using animal models in males, but the underlying mechanisms in females are less clear. We found that HF with normal salt (60% kcal from fat with 0.3% NaCl) feeding significantly and equally increases mean arterial blood pressure (MAP) in male and female Dahl salt sensitive rats compared to normal fat (NF) normal salt feeding (10% kcal from fat with 0.3% NaCl) for 24–26 weeks starting at weaning (3 weeks of age). MAP in HF rats was similar to MAP in NF rats at 10 weeks of feeding. At 17 weeks, MAP was significantly higher in HF than in NF rats. MAP was dramatically higher (~35 mmHg) in HF rats after 24 weeks of feeding. We determined if the mechanisms responsible for renal inflammation/injuries are similar in males and females. Renal tissues were taken from rats at 10, 17 and 24 weeks of feeding. Renal injury was histologically characterized. Renal inflammation was identified by the infiltration of macrophages (CD68) and T cells (CD3) in cortex and medulla. At 10 weeks, females did not show renal injuries, all males showed low grade renal injury with higher CD68 cells than females. CD3 cells were similar in males and females at lower levels. At 17 weeks, HF males displayed more severe renal injury compared to NF males and all females. CD68 and CD3 cells in males were unchanged compared to their 10 week values, females had similar CD68 and higher CD3 cells compared to males. At 24 weeks, HF males displayed much more severe renal injury with higher CD68 cells than NF males and all females. All males had significantly increased CD3 cells compared with their 10 and 17 weeks values. HF females had lower grade renal injury and lower CD68 cells than HF males, and CD3 cells were similar to males. The expression of renal proliferating cell nuclear antigen (PCNA, a cellular proliferation marker) was similar in all males and females at 17 weeks, and significantly and equally increased in all HF rats at 24 weeks. Expression of renal phospho‐S6 ribosomal protein (pS6, a surrogate marker of mTORC1 activity) was significantly higher in all females compared with all males at 17 weeks, but similar in all rats at 24 weeks. All females had higher expression of phospho‐Akt (pAkt, the canonical readout of mTORC2 activity) than males at 17 and 24 weeks. HF feeding increased pAkt expression only in females at 24 weeks. At 24 weeks, neither HF males nor females had larger final body weights than their respective NF groups. No differences in plasma levels of fasting glucose, insulin, leptin, cholesterol, triglycerides, creatinine or BUN were found between HF versus NF males or females. All females had higher plasma albumin levels than males at 17 weeks, but not at 24 weeks. Our studies show that HF diet promotes hypertension equally in Dahl salt sensitive males and females without causing overt metabolic dysfunction in either sex. In this setting, females are less prone to develop hypertension associated renal injury than males. Females do develop renal inflammation, however, the time course and types of immune cell infiltration are different from what is observed in males. Higher activities of renal mTORC2 and other immune regulatory mechanisms may protect against renal injury in females by increasing cell survival and improving the injured tissue repair.Support or Funding InformationNIH NHLBI 2P01HL070687This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.