Female mice are protected against the renal pro‐inflammatory effects of a high‐salt diet during diabetes

High‐salt diet and hypertension are major contributors to diabetic nephropathy and predispose to end‐stage renal disease. In addition, studies in both humans and animal models of diabetes demonstrated that males have higher incidence of diabetic kidney disease compared to females. Objective We aim to determine the contribution of a high salt diet to the development of renal inflammation associated with diabetes in female versus male diabetic mice. Methods Four‐month‐old female and male db/db mice (a model of type 2 diabetes) and non‐diabetic controls were exposed to either a high (4% NaCl w/w) or control (0.4% NaCl w/w) diet for 3 weeks (n=4). Systolic blood pressure (SBP) was measured by the tail‐cuff method. At the end of the protocol, mice were euthanized, and kidneys were preserved to assess renal inflammation. Results A high salt diet did not modify the blood pressure in any experimental group. At the beginning of the high salt diet, SBP was 99 ± 8 mmHg in diabetic females and 100 ± 3 mmHg in diabetic males. After 3 weeks of high salt, SBP was 101 ± 4 mmHg in diabetic females and 106 ± 2 mmHg in diabetic males (P=NS). However, male diabetic mice exposed to high salt displayed higher abundance of renal TNFα (1.8‐fold increase, P <0.001), IL‐6 (1.9 fold‐increase, P <0.01) and IL‐1β (2.1‐fold increase, P <0.05) compared to equally treated diabetic females. Further, male diabetic mice displayed higher expression of renal NLRP3 inflammasome components such as Pro‐caspase‐1 (2.6‐fold increase, P <0.01), caspase‐1 (2.2‐fold increase, P <0.05) and the adaptor protein ASC (2.3‐fold increase, P <0.05) compared to female diabetic mice. Finally, the anti‐inflammatory cytokine IL‐10 was decreased in diabetic males exposed to a high salt diet compared to diabetic males receiving a control diet (from 563 ± 23 to 411 ± 21 pg/mg kidney protein, P <0.05). In female diabetic mice, IL‐10 remained unchanged. Both female and male non‐diabetic mice displayed no changes in response to a 3‐week high salt diet. Conclusion Even in the absence of salt‐sensitive hypertension, male diabetic mice are more susceptible to the renal pro‐inflammatory effects of a high‐salt diet compared to female diabetic mice. Support or Funding Information This study was supported by NIH R01HL142672, AHA 16SDG30130015, and P30 DK063491 (JFG); NIH R01HL110353 and AHA 17GRNT32580000 (KEB). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .