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Inhibition of the inflammasome ameliorates orthologous polycystic kidney disease

ABSTRACT: ADPKD is the most common genetic renal disease, leading to renal failure in the vast majority of affected individuals. Standard therapy consists of blood pressure control and salt restriction. Tolvaptan further delays renal failure but side effects prevent its widespread use. Novel therapeutic approaches are needed. Recent evidence has identified inflammation as an important driver of ADPKD. Here we show a strong inflammatory signature in transcriptomes of early ADPKD in the mouse. IL1β and IL18, effectors of inflammasome activation, are among the top upregulated transcripts. Inflammasomes act as part of the innate immune response to danger signals, including crystals. Induction of calcium oxalate crystals through dietary intervention in Pkd1 mutant mice aggravated the cystic phenotype. Treatment of Pkd1 mutant mice with the inflammasome inhibitor MCC950 significantly ameliorated the ADPKD phenotype. Analogous results were obtained through genetic silencing of the essential inflammasome component Asc in ADPKD mice. Interference with inflammasome activation in the ADPKD animals resulted in better renal function and decreased IL18 excretion in the urine. These findings identify inflammasome inhibition as a promising concept for the treatment of ADPKD.

ORGANISM(S): Mus musculus

PROVIDER: GSE273186 | GEO | 2025/11/03

REPOSITORIES: GEO

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Project description:Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple fluid-filled cysts that destroy the kidney architecture resulting in end-stage renal failure. Mutations in the ADPKD genes PKD1 and PKD2 account for nearly all the cases of ADPKD. Increased cell proliferation is one of the key features of the disease. Several studies indicated that polycystin-1, the product of PKD1, regulates cellular proliferation through various signaling pathways, but little is known about the role played by polycystin-2, the product of PKD2. Recently, it was reported that as with polycystin-1, polycystin-2 can acts as a negative regulator of cell growth by modulating the levels of the cyclin-dependent kinase inhibitor, p21 and the activity of the cyclin-dependent kinase 2, Cdk2. In this study we utilized different kidney cell lines expressing wild-type and mutant PKD2 as well as primary tubular epithelial cells isolated from a PKD transgenic rat to further explore the contribution of the p21/Cdk2 pathway in ADPKD proliferation. Surprisingly, over-expression of wild-type PKD2 in renal cell lines failed to inactivate Cdk2 activity and consequently had no effect on cell proliferation. On the other hand, expression of mutated PKD2 augmented proliferation only in the primary tubular epithelial cells of a rat model but this was independent of STAT-1/p21 pathway. Genome-wide expression analysis in these cells revealed that expression of the cyclin-dependent kinase inhibitor, p57 is downregulated, while p21 remains unchanged. This p57 reduction is accompanied by an increase in Cdk2 levels. Our results indicate the probable involvement of p57 on epithelial cell proliferation in polycystic kidney disease. In addition, it confirms that PKD2-induced proliferation is a multifactorial process. We used microarrays to study the modulation of gene expression by mutated PKD2 in the primary tubular epithelial cells of a transgenic rat mode Keywords: transgene Gene expression in the primary tubular epithelial of a transgenic rat mode with mutated PKD2 was compared with that of SD control rats

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Inhibition of the inflammasome ameliorates orthologous polycystic kidney disease

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