期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 32, 期 5, 页码 1131-1149出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2020081112
关键词
sex differences; diabetes; obesity; hypertension; renin angiotensin system; inflammation; interleukin-6; sodium transporters
资金
- National Heart, Lung, and Blood Institute [R01HL142672, P01HL129941]
- National Institute of Diabetes and Digestive and Kidney Diseases [P30DK063491, T32DK007770]
- AHA [16SDG30130015, 17GRNT33661206]
In male db/db mice with type 2 diabetes, salt-sensitive hypertension was observed after exposure to a high-salt diet, while female db/db mice did not develop this condition. The salt-sensitive hypertension in male mice was associated with impaired ENaC downregulation, accompanied by more immune-cell infiltration and higher levels of proinflammatory cytokines. Blocking inflammation prevented the development of salt sensitivity in male db/db mice.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据