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

Autor: Kaverina N; Division of Nephrology, University of Washington, Seattle, WA 98109, USA., Schweickart RA; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA., Chan GC; Department of Medicine, Division of Nephrology, National University Hospital, Singapore., Maggiore JC; Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA., Eng DG; Division of Nephrology, University of Washington, Seattle, WA 98109, USA., Zeng Y; Department of Chemistry, University of Washington, Seattle, WA 98109, USA., McKinzie SR; Division of Nephrology, University of Washington, Seattle, WA 98109, USA., Perry HS; Department of Chemistry, University of Washington, Seattle, WA 98109, USA., Ali A; Department of Chemistry, University of Washington, Seattle, WA 98109, USA., O'Connor C; Division of Nephrology, University of Michigan, Ann Arbor, MI 48109, USA., Pereira BMV; Division of Nephrology, University of Washington, Seattle, WA 98109, USA., Theberge AB; Department of Chemistry, University of Washington, Seattle, WA 98109, USA., Vaughan JC; Department of Chemistry, University of Washington, Seattle, WA 98109, USA.; Department of Physiology and Biophysics, University of Washington, Seattle, WA 98109, USA., Loretz CJ; Division of Nephrology, University of Washington, Seattle, WA 98109, USA., Chang A; Department of Pathology, University of Chicago, Chicago, IL 60637, USA., Hukriede NA; Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA., Bitzer M; Division of Nephrology, University of Michigan, Ann Arbor, MI 48109, USA., Pippin JW; Division of Nephrology, University of Washington, Seattle, WA 98109, USA., Wessely O; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA., Shankland SJ; Division of Nephrology, University of Washington, Seattle, WA 98109, USA.; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
Jazyk: angličtina
Zdroj: Aging [Aging (Albany NY)] 2023 Jul 23; Vol. 15 (14), pp. 6658-6689. Date of Electronic Publication: 2023 Jul 23.
DOI: 10.18632/aging.204897
Abstrakt: 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.
Databáze: MEDLINE