Endothelial dysfunction exacerbates kidney dysfunction in ageing kidney via activation of inflammasome.

Background: Ageing affects the function of the immune system and leads to immunosenescence, which is characterized by defective immune responses and increased systemic inflammation (also termed inflammageing). Inflammageing is maladaptive and results from multiple mechanisms, including aberrant inflammasome activation. The ASC is an essential component of inflammasomes that activates caspase 1. Endothelial dysfunction is also a common pathophysiologic mechanism of age-related organ damage. Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is an important mediator in the maintenance of vascular homeostasis. We have reported that the eNOS-NO pathway attenuates the progression of kidney injury via suppression of inflammasomes. However, the relationship between the eNOS-NO pathway and inflammageing in the kidney remains unclear. To determine if the eNOS-NO pathway attenuates kidney damage via the regulation of inflammasome activation in ageing kidneys, we used eNOS-deficient mice (eNOSKO) and eNOS-ASC double-knockout mice (eNOS-ASC-DKO). Methods: Wild-type mice (WT) and eNOSKO were used to determine the role of the eNOS-NO pathway in ageing kidneys. WT and eNOSKO were sacrificed at 18 months of age to harvest kidney tissue. The localization of inflammasome activation in the kidney was evaluated with immunohistochemical analyses. To determine the role of inflammasomes in ageing kidneys, we generated eNOS-ASC-DKO. The mRNA expression of inflammasome components were determined in isolated glomeruli. Results: The glomerular injury was more exacerbated in eNOSKO-18 M than in WT-18 M. In the immunohistochemical analyses, the expression of ASC coexisted with the macrophages detected by F4/80 staining in eNOSKO-18 M. These data suggested that the inflammasome activation was located in the macrophages. In the isolated glomeruli, the mRNA of the inflammasome components was higher in eNOSKO-18 M than in WT-18 M. The glomerular damage and tubulointerstitial damage were ameliorated in eNOS-ASC-DKO-18 M compared to eNOSKO-18 M. In summary, in eNOS-deficient mice, inflammasomes were activated in macrophages, and interstitial fibrosis was exacerbated. However, in eNOS-ASC-DKO-18 M mice, the tubulointerstitial damage was attenuated. Conclusion: Endothelial NOS/NO signaling ameliorates kidney damage in the aging process via the modulation of inflammageing associated with inflammasome-activation.