Abstract
Chronic kidney disease is a common problem in the elderly and is associated with increased mortality. We have reported on the role of nitric oxide, which is generated from endothelial nitric oxide synthase (eNOS), in the progression of aged kidneys. To elucidate the role of endothelial dysfunction and the lack of an eNOS-NO pathway in ageing kidneys, we conducted experiments using eNOS and ASC-deficient mice. C57B/6 J mice (wild type (WT)), eNOS knockout (eNOS KO), and ASC knockout (ASC KO) mice were used in the present study. Then, eNOS/ASC double-knockout (eNOS/ASC DKO) mice were generated by crossing eNOS KO and ASC KO mice. These mice were sacrificed at 17−19 months old. The Masson positive area and the KIM-1 positive area tended to increase in eNOS KO mice, compared with WT mice, but not eNOS/ASC DKO mice. The COX-positive area was significantly reduced in eNOS KO mice, compared with WT and eNOS/ASC DKO mice. To determine whether inflammasomes were activated in infiltrating macrophages, the double staining of IL-18 and F4/80 was performed. IL-18 and F4/80 were found to be co-localised in the tubulointerstitial areas. Inflammasomes play a pivotal role in inflammaging in ageing kidneys. Furthermore, inflammasome activation may accelerate cellular senescence via mitochondrial dysfunction. The importance of endothelial function as a regulatory mechanism suggests that protection of endothelial function may be a potential therapeutic target.
Highlights
Chronic kidney disease (CKD) is a common problem in the elderly and is associated with increased mortality
Serum creatinine was significantly elevated in endothelial nitric oxide synthase (eNOS) KO mice, compared with WT mice (Figure 1b)
Body weight was significantly lower in eNOS knockout (eNOS KO) and eNOS/ASC DKO mice than WT mice
Summary
Chronic kidney disease (CKD) is a common problem in the elderly and is associated with increased mortality. Arteriosclerosis-related renal morphological changes, such as an increased number of hyalinised glomeruli, a decreased number of total glomeruli, tubulointerstitial fibrosis, and fibrous thickening of the vascular endothelium, are increased with ageing These morphological changes are associated with endothelial dysfunction. NO production is impaired in both CKD [7] and the ageing kidney [8], coinciding with the progression of renal injury and decreased renal plasma flow. These facts suggested that endothelial dysfunction, that is, the lack of an eNOS-NO pathway, accelerates ageing-related kidney dysfunction. Inflammasome activation is important for prolonging inflammation in kidney diseases, resulting in fibrotic change. The relationship between inflammasome-related inflammation and the eNOS-NO pathway has not been elucidated
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