Research Paper Volume 15, Issue 14 pp 6658—6689
Inhibiting NLRP3 signaling in aging podocytes improves their life- and health-span
- 1 Division of Nephrology, University of Washington, Seattle, WA 98109, USA
- 2 Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA
- 3 Department of Medicine, Division of Nephrology, National University Hospital, Singapore
- 4 Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
- 5 Department of Chemistry, University of Washington, Seattle, WA 98109, USA
- 6 Division of Nephrology, University of Michigan, Ann Arbor, MI 48109, USA
- 7 Department of Physiology and Biophysics, University of Washington, Seattle, WA 98109, USA
- 8 Department of Pathology, University of Chicago, Chicago, IL 60637, USA
- 9 Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
Received: April 7, 2023 Accepted: July 6, 2023 Published: July 23, 2023
https://doi.org/10.18632/aging.204897How to Cite
Copyright: © 2023 Kaverina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
The decrease in the podocyte’s lifespan and health-span that typify healthy kidney aging cause a decrease in their normal structure, physiology and function. The ability to halt and even reverse these changes becomes clinically relevant when disease is superimposed on an aged kidney. RNA-sequencing of podocytes from middle-aged mice showed an inflammatory phenotype with increases in the NLRP3 inflammasome, signaling for IL2/Stat5, IL6 and TNF, interferon gamma response, allograft rejection and complement, consistent with inflammaging. Furthermore, injury-induced NLRP3 signaling in podocytes was further augmented in aged mice compared to young ones. The NLRP3 inflammasome (NLRP3, Caspase-1, IL1β IL-18) was also increased in podocytes of middle-aged humans. Higher transcript expression for NLRP3 in human glomeruli was accompanied by reduced podocyte density and increased global glomerulosclerosis and glomerular volume. Pharmacological inhibition of NLRP3 with MCC950, or gene deletion, reduced podocyte senescence and the genes typifying aging in middle-aged mice, which was accompanied by an improved podocyte lifespan and health-span. Moreover, modeling the injury-dependent increase in NLRP3 signaling in human kidney organoids confirmed the anti-senescence effect of MC9950. Finally, NLRP3 also impacted liver aging. Together, these results suggest a critical role for the NLRP3 inflammasome in podocyte and liver aging.
Abbreviations
GFP: glomerular filtration rate; GSEA: gene set enrichment analysis; NLRP: nod-like receptor protein; NLRP3: NLR family pyrin domain containing 3; EGFP: enhanced green fluorescent protein; SASP: senescent-associated secretory phenotype; FSGS: focal segmental glomerulosclerosis; DAMPs: damage- associated molecular patterns; PAMPs: pathogen-associated molecular patterns; MCC950: 1-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-3-(4-(2-hydroxypropan-2-yl) furan-2-yl) sulfonylurea; ERS: endoplasmic reticulum stress.