Renal Inflammation Induces Salt Sensitivity in Male db/db Mice through Dysregulation of ENaC.
Publication Year:
2021
PubMed ID:
33731332
Funding Grants:
Public Summary:
High blood pressure (hypertension) often makes diabetic kidney disease worse, especially in people with type 2 diabetes. Men are known to have a higher risk than women, but the reasons for this difference aren’t well understood.
In this study, researchers looked at male and female diabetic mice fed a high-salt diet. They found that male mice developed high blood pressure, while female mice did not, even though both had diabetes and ate the same salty diet.
In male mice, the kidneys didn’t properly turn off a protein called ENaC, which controls how much salt the body keeps. Normally, a high-salt diet should lower ENaC activity to get rid of extra salt—but that didn’t happen in males. The male mice also showed more inflammation and more immune cells in their kidneys than females.
When researchers blocked inflammation—either with an anti-inflammatory drug or by reducing a molecule called IL-6—the male mice no longer developed high blood pressure from the salty diet.
Scientific Abstract:
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.