Renal Inflammation Induces Salt Sensitivity in Male db/db Mice through Dysregulation of ENaC

Significance Statement Men with diabetes have higher incidence of renal disease and hypertension than premenopausal women with diabetes. A mouse model investigated the mechanisms that predispose to salt-sensitive hypertension during diabetes. Male, 34-week-old, diabetic mice display hypertension when exposed to a high-salt diet, whereas females remain normotensive. Hypertension in males was associated with greater renal inflammation and no downregulation of the epithelial sodium channel (ENaC) compared with females. Blocking inflammation prevented the development of salt sensitivity and restored the normal regulation of ENaC in male diabetic mice. These findings indicate that inflammation is a key contributor to the sexual dimorphism associated with diabetic nephropathy. Understanding the mechanisms behind diabetes-associated salt sensitivity is critical to tailor rational therapies in a sex-specific manner. Background Hypertension is considered a major risk factor for the progression of diabetic kidney disease. Type 2 diabetes is associated with increased renal sodium reabsorption and salt-sensitive hypertension. Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the renal mechanisms that predispose to salt sensitivity during diabetes and whether sexual dimorphism is associated with these mechanisms remains unknown. Methods Female and male db/db mice exposed to a high-salt diet were used to analyze the progression of diabetic kidney disease and the development of hypertension. Results Male, 34-week-old, db/db mice display hypertension when exposed to a 4-week high-salt treatment, whereas equivalently treated female db/db mice remain normotensive. Salt-sensitive hypertension in male mice was associated with no suppression of the epithelial sodium channel (ENaC) in response to a high-salt diet, despite downregulation of several components of the intrarenal renin-angiotensin system. Male db/db mice show higher levels of proinflammatory cytokines and more immune-cell infiltration in the kidney than do female db/db mice. Blocking inflammation, with either mycophenolate mofetil or by reducing IL-6 levels with a neutralizing anti–IL-6 antibody, prevented the development of salt sensitivity in male db/db mice. Conclusions The inflammatory response observed in male, but not in female, db/db mice induces salt-sensitive hypertension by impairing ENaC downregulation in response to high salt. These data provide a mechanistic explanation for the sexual dimorphism associated with the development of diabetic kidney disease and salt sensitivity.