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.

• Authors: Yoshihisa Wada, Reina Umeno, Hajime Nagasu, Megumi Kondo, Atsuyuki Tokuyama, Hiroyuki Kadoya, Kengo Kidokoro, Shun'ichiro Taniguchi, Masafumi Takahashi, Tamaki Sasaki, Naoki Kashihara
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 17 (Aug 27 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34502177 (Publication Type: Journal Article)

Chemical References

• Inflammasomes
• Nitric Oxide
• Nitric Oxide Synthase Type III

Topics

• Aging
• Animals
• Endothelium (enzymology, metabolism, physiopathology)
• Inflammasomes
• Kidney (physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Mitochondria (metabolism, physiology)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Vascular Diseases (physiopathology)