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Abstract: TH-PO959

Endothelial Dysfunction Exacerbates Renal Tubular Cell Injury Through Inflammasome Activation in a Hypertensive Mouse Model

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic

Authors

  • Sogawa, Yuji, Kawasaki Medical School, Kurashiki, Japan
  • Nagasu, Hajime, Kawasaki Medical School, Kurashiki, Japan
  • Kondo, Megumi, Kawasaki Medical School, Kurashiki, Japan
  • Wada, Yoshihisa, Kawasaki Medical School, Kurashiki, Japan
  • Kadoya, Hiroyuki, Kawasaki Medical School, Kurashiki, Japan
  • Kidokoro, Kengo, Kawasaki Medical School, Kurashiki, Japan
  • Satoh, Minoru, Kawasaki Medical School, Kurashiki, Japan
  • Sasaki, Tamaki, Kawasaki Medical School, Kurashiki, Japan
  • Kashihara, Naoki, Kawasaki Medical School, Kurashiki, Japan
Background

Chronic inflammation is a common pathway of progressive kidney diseases. One of the mechanism in forming chronic inflammation is NLRP3 inflammasome activation. We reported that aldosterone induced hypertension progress tubular interstitium injury via NLRP3 inflammasome activation. However, it is unclear how NLRP3 inflammasome is regulated in the kidney. On the other hand, it is reported that nitric oxide(NO) derived from iNOS suppress inflammasome activation in macrophage. So, we investigated whether or not NO derived from eNOS suppress inflammasome activation in hypertensive kidney disease because it is well known that endothelial dysfunction promotes progressive kidney disease.

Methods

Six weeks male C57BL/6 mice (WT) and eNOS deficient mice (eNOSKO) were used. These mice were divided into four groups (WT, WT-Ald, eNOS, and eNOS-Ald). Aldosterone (Ald) was continuously administered for four weeks by infusion pump. Next, eNOS/ASC double deficient mice (eNOS/ASC DKO) were generated to investigated whether inhibition of inflammasome activation can reduce kidney injury caused by endothelial dysfunction. Finally, we explored the molecular mechanisms underlying the regulation of inflammasome activation by endothelial dysfunction. Bone marrow-derived macrophages (BMDMs) were stimulated with ATP after priming LPS and simultaneously primed with S-nitrosoglutathione (GSNO) as an NO donor or Bay41-2272 as a sGC stimulator.

Results

NLRP3 inflammasome activation was increased in the kidneys of the eNOS-deficient mice, and tubulointerstitial fibrosis was accelerated. Suppression of inflammasome activation by knocking out ASC prevented tubulointerstitial injury in the eNOS knockout mice, indicating that the eNOS-NO pathway is involved in the development of kidney dysfunction through acceleration of NLRP3 inflammasome in macrophages. ATP stimulation with LPS priming caused NLRP3 inflammasome-dependent cell death and IL1beta secretion. While GSNO inhibited this activation, it did not affect the sGC stimulator. This data suggests that NO can suppress NLRP3 inflammasome activation directly in macrophages.

Conclusion

eNOS-NO pathway could be a therapeutic target for the treatment of chronic kidney disease associated with endothelial dysfunction.

Funding

  • Government Support - Non-U.S.