Abstract 13320: Endothelial Dysfunction by ENOS Deficiency Develops Salt Sensitivity and Renal Injury via the Activation of Intraglomerular Renin-Angiotensin System (RAS) and Oxidative Stress
Aim: We examined how endothelial dysfunction develop salt-induced renal injuries in vivo.
Methods: (1) Wild-type and eNOS knockout (eNOS−/−) mice were fed normal- or high-salt diets. We measured urinary albumin excretion (UAE) levels weekly and analysed glomerular histopathology at 1 and 4 wks after salt loading. (2) eNOS−/− mice fed high-salt diets were divided into vehicle, irbesartan and tempol to examine the involvement of RAS and oxidative stress in renal injury.
Results: (1) Excessive salt intake significantly increased urinary nitrate/nitrite (NOx) excretion levels in wild-type mice and activated eNOS phoshorylation in the glomerular endothelium. Salt intake did not increase UAE and nor did it cause glomerular damage in wild-type mice. On the other hand, the increase of salt-induced urinary NOx was significantly reduced in eNOS−/− compared with wild-type mice. Salt intake markedly increased UAE and glomerular superoxide production in eNOS−/−. Salt intake also significantly enhanced glomerular macrophage infiltration, upregulated MCP-1 mRNA expression, and caused glomerulosclerosis in eNOS−/− at 4 wks after salt loading. Reduced NO production thereby worsen salt-induced renal damage. Only in eNOS−/− did salt intake markedly increase urinary angiotensinogen (AGT) excretion levels; moreover, AGT protein levels specifically located in the endothelial and mesangial cells in the glomeruli were significantly increased earlier than inflammatory responses occured. Salt intake significantly increased Ang II protein in eNOS−/− glomeruli. (2) Irbesartan or tempol therapy, independently of BP, significantly ameliorated the increase of UAE, AGT upregulation in glomeruli and glomerular superoxide by salt intake. Salt-induced renal injuries at 4 wks after salt-loading, such as the exacerbation of albuminuria, glomerular macrophage infiltration, MCP-1 mRNA upregulation, or glomerulosclerosis, were all significantly decreased by either treatment. Thus, eNOS dysfunction develops salt-induced renal injuries via the upregulation of intraglomerular AGT and the increase of oxidative stress.
Conclusion: The impairment of endothelial function develops salt-induced albuminuria via the activation of intrarenal RAS and oxidative stress.
- © 2010 by American Heart Association, Inc.