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Research Paper|Volume 15, Issue 14|pp 6658—6689

Inhibiting NLRP3 signaling in aging podocytes improves their life- and health-span

Natalya Kaverina1, R. Allen Schweickart2, Gek Cher Chan3, Joseph C. Maggiore4, Diana G. Eng1, Yuting Zeng5, Sierra R. McKinzie1, Hannah S. Perry5, Adilijiang Ali5, Christopher O’Connor6, Beatriz Maria Veloso Pereira1, Ashleigh B. Theberge5, Joshua C. Vaughan5,7, Carol J. Loretz1, Anthony Chang8, Neil A. Hukriede4, Markus Bitzer6, Jeffrey W. Pippin1, Oliver Wessely2, Stuart J. Shankland1,9
  • 1Division of Nephrology, University of Washington, Seattle, WA 98109, USA
  • 2Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA
  • 3Department of Medicine, Division of Nephrology, National University Hospital, Singapore
  • 4Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
  • 5Department of Chemistry, University of Washington, Seattle, WA 98109, USA
  • 6Division of Nephrology, University of Michigan, Ann Arbor, MI 48109, USA
  • 7Department of Physiology and Biophysics, University of Washington, Seattle, WA 98109, USA
  • 8Department of Pathology, University of Chicago, Chicago, IL 60637, USA
  • 9Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
* Co-senior authors
Received: April 7, 2023Accepted: July 6, 2023Published: July 23, 2023
https://doi.org/10.18632/aging.204897

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.