Endothelial Dysfunction Accelerates Impairment of Mitochondrial Function in Ageing Kidneys via Inflammasome Activation

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.

Increased Prolylcarboxypeptidase Expression Can Serve as a Biomarker of Senescence in Culture

“…As NO is rapidly used up, eNOS remains steady for several late, senescent passages. Our results supported previous findings with NO in aging cells [36], showing that there is also a rapid increase in eNOS over time, followed by a slow decrease. These results indicated that the upregulation of eNOS mRNA was consistent with the increase in kallikrein formation (Figure 1) and elevation of PRCP enzyme activity (Figure 2), suggesting that PRCP might play a key role in protecting cell survival via scavenging ROS.…”

“…Prior studies have shown that the endothelial senescence is triggered by numerous senescence stressors including oxidative stress and mitochondrial dysfunction [36,69]. In a previous work, we showed that overexpression of PRCP enhanced certain markers of mitochondrial autophagy [67], the process by which damaged mitochondria are removed under mitochondrial toxicity conditions [70], or may help to delay cell death.…”

The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

“…In addition to oxidative stress, nitrosative stress is also vital for septic kidney. The source of nitrosative stress, NO, is a chemical synthesized by nitric oxide synthase (NOS), with great vasodilation ability but a short half-life (158)(159)(160). There are currently three types of NOS: nNOS, iNOS, and eNOS.…”