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Inhibiting NLRP3 signaling in aging podocytes improves their life- and health-span
Natalya Kaverina1, R Allen Schweickart2, Gek Cher Chan3
1Division of Nephrology, University of Washington, Seattle, WA 98109, USA.
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.
Insights
The NLRP3 inflammasome drives kidney podocyte aging and dysfunction. Inhibiting NLRP3 rejuvenates podocyte health and function, offering a potential therapeutic target for aging kidneys.
Area of Science:
- Nephrology
- Immunology
- Aging Research
Background:
- Kidney aging diminishes podocyte lifespan and function, complicating age-related kidney diseases.
- Inflammaging, characterized by chronic inflammation, is a hallmark of aging and contributes to organ dysfunction.
Purpose of the Study:
- To investigate the role of the NLRP3 inflammasome in podocyte aging and its potential as a therapeutic target.
- To determine if inhibiting NLRP3 can ameliorate age-related changes in podocytes and kidney function.
Main Methods:
- RNA-sequencing of podocytes from middle-aged mice to identify aging-related inflammatory pathways.
- Assessing NLRP3 inflammasome activation in podocytes from aged mice and middle-aged humans.
- Utilizing pharmacological inhibition (MCC950) and gene deletion of NLRP3 in mice.
- Modeling injury-induced NLRP3 signaling in human kidney organoids.
Main Results:
- Middle-aged mice podocytes exhibited an inflammatory phenotype with increased NLRP3 inflammasome activity, consistent with inflammaging.
- NLRP3 inflammasome components were elevated in human podocytes and correlated with reduced podocyte density and glomerulosclerosis.
- NLRP3 inhibition in aged mice reduced podocyte senescence and improved kidney aging markers.
- MCC950 demonstrated anti-senescence effects in human kidney organoids.
Conclusions:
- The NLRP3 inflammasome plays a critical role in podocyte aging and kidney dysfunction.
- Targeting the NLRP3 inflammasome with MCC950 offers a promising therapeutic strategy to combat kidney aging and related pathologies.
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