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

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.

Podocyte Senescence and Aging

“…17 This includes podocytes that undergo cell cycle arrest on differentiation. [18][19][20][21][22] Thus, at least in postmitotic cells, the pathways required for cell cycle arrest and those for senescence are independent. 17 Finally, it is important to emphasize that senescence is a double-edged sword.…”

“…In podocytes, senescence increases with healthy aging, but also can undergo stress-induced senescence during disease. [18][19][20][21] Because podocytes are terminally differentiated epithelial cells, they have exited the cell cycle and reside in G 0 ; thus, the criteria qualifying them as senescent are different from proliferating cells. Table 2 summarizes and contrasts these characteristics by comparing non-senescent and senescent podocytes as well as senescent, proliferating epithelial cells.…”

“…Moreover, in microdissected human glomeruli, increased NLRP3 mRNA expression was associated with an increased percentage of globally sclerosed glomeruli, higher glomerular volume, and reduced podocyte density. 62 More importantly, the NLRP3 inflammasome plays a similarly important role in podocyte aging as it does for glomerular disease under non-aged conditions. [73][74][75][76][77][78][79][80][81] Inhibiting its activity in middle-aged mice with the NLRP3 inhibitor MCC950 and deleting NLRP3 genetically slowed aging, as evidenced by a higher podocyte density and higher levels of health span markers, reduced podocyte senescence, and SASP.…”

“…Moreover, ectopic expression of PD-1 in cultured podocytes triggers a partially Caspase-3–dependent apoptosis.Other forms of inflammation: Gene set enrichment analysis of aging mRNAseq data from aging mice implicates additional inflammatory pathways, such as IL2, IL6, INF γ , TNF, and complement signaling. 62 Yet, whether and how they affect glomerular aging still needs to be assessed.…”

“…Further studies are needed to better understand this pathway as a mechanism of podocyte aging.NLRP3 inflammasome inhibitors: Pharmacologically inhibiting the increase in NLRP3 in middle-aged podocytes with MCC950 reduced their senescence and improved many measures of podocyte life span and health span. 62 …”