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Kidney Week

Abstract: PO2505

The eNOS–NO Pathway Attenuates the Progression of Age-Related Kidney Diseases via Suppression of C/EBPβ-Associated Inflammaging

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Umeno, Reina, Kawasaki Medical School Department of Nephrology and Hypertension, Kurashiki, Okayama, Japan
  • Nagasu, Hajime, Kawasaki Medical School Department of Nephrology and Hypertension, Kurashiki, Okayama, Japan
  • Wada, Yoshihisa, Kawasaki Medical School Department of Nephrology and Hypertension, Kurashiki, Okayama, Japan
  • Kadoya, Hiroyuki, Kawasaki Medical School Department of Nephrology and Hypertension, Kurashiki, Okayama, Japan
  • Kidokoro, Kengo, Kawasaki Medical School Department of Nephrology and Hypertension, Kurashiki, Okayama, Japan
  • Kashihara, Naoki, Kawasaki Medical School Department of Nephrology and Hypertension, Kurashiki, Okayama, Japan
Background

Chronic kidney disease (CKD) is a very common clinical problem in elderly patients and is associated with increased mortality. As life expectancy continues to improve worldwide, the prevalence of comorbidities and risk factors, such as hypertension and diabetes, that predispose this population to a high burden of CKD is rising . Chronic inflammation (inflammaging) is also an important cause of age-related organ damage, such as kidney disease, and we hypothesized that endothelial dysfunction accelerates the progression of age-related kidney injury.

Methods

We evaluated the anti-inflammatory effects of nitric oxide (NO) as an endothelial function in bone marrow–derived macrophages (BMDM) using in vitro experiments. BMDM derived from Wild Type (C57BL/6J; WT) were stimulated through NLRP3 inflammasome activation using LPS-ATP, and the IL-1β secretion was examined. To determine the importance of inflammasome activation in age-related kidney diseases, we used mice deficient in apoptosis-associated speck-like protein containing CARD (ASC) —which is an essential molecule for inflammasome activation—in vivo. We evaluated those mice (ASCKO), eNOS knockout (eNOSKO) mice, and eNOS-ASC double-knockout mice (eNOS-ASC-DKO).

Results

S-nitrosoglutathione (GSNO) attenuated the NLRP3 inflammasome activation that followed treatment with LPS-ATP. This indicates that NO directly inhibits NLRP3 inflammasome activation. GSNO also decreased the expression of inflammasome-related genes. To investigate the detailed mechanisms (epigenetic regulation), we performed ATAC-seq using BMDM. The binding region of the transcription factor CCAAT/enhancer-binding protein (C/EBP) β was significantly closed in the LPS+GSNO, compared with the LPS; it has recently been reported that C/EBP is associated with the NLRP3 inflammasome and is activated in aging kidneys. These mice were sacrificed at 15 months of age; the glomerular injury was found to be exacerbated, and serum Crn was elevated in the eNOSKO-15M, but not in the WT-15M. These changes were improved in the eNOS-ASC-DKO-15M.

Conclusion

The eNOS–NO pathway ameliorated the progression of renal injury by regulating the inflammaging of the aging kidney. NO directly inhibits NLRP3 inflammasome activation via the suppression of C/EBP β activation.