Inflammatory Mediators in the Progression of Renal Cystic Disease

GardnerJr., Kenneth D.; Burnside, Janet S.; Elzinga, Lawrence W.; Locksley, Richard M.

doi:10.1007/978-3-662-35158-1_160

Cited by 2 publications

(2 citation statements)

References 9 publications

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“…This analysis revealed measurable levels of both cytokines (ranging from 46 to 93 pg/ml for IL-1β and 34-673 pg/ml for 1L-18) in all samples. These findings are similar to those obtained in previous studies (Gardner et al, 1991;Parikh et al, 2012). While there are non-canonical…”

Section: Resultssupporting

confidence: 93%

Caspase-1 and the inflammasome promote polycystic kidney disease progression

Swenson-Fields

Ward

Lopez

et al. 2022

Front. Mol. Biosci.

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We and others have previously shown that the presence of renal innate immune cells can promote polycystic kidney disease (PKD) progression. In this study, we examined the influence of the inflammasome, a key part of the innate immune system, on PKD. The inflammasome is a system of molecular sensors, receptors, and scaffolds that responds to stimuli like cellular damage or microbes by activating Caspase-1, and generating critical mediators of the inflammatory milieu, including IL-1β and IL-18. We provide evidence that the inflammasome is primed in PKD, as multiple inflammasome sensors were upregulated in cystic kidneys from human ADPKD patients, as well as in kidneys from both orthologous (PKD1RC/RC or RC/RC) and non-orthologous (jck) mouse models of PKD. Further, we demonstrate that the inflammasome is activated in female RC/RC mice kidneys, and this activation occurs in renal leukocytes, primarily in CD11c+ cells. Knock-out of Casp1, the gene encoding Caspase-1, in the RC/RC mice significantly restrained cystic disease progression in female mice, implying sex-specific differences in the renal immune environment. RNAseq analysis implicated the promotion of MYC/YAP pathways as a mechanism underlying the pro-cystic effects of the Caspase-1/inflammasome in females. Finally, treatment of RC/RC mice with hydroxychloroquine, a widely used immunomodulatory drug that has been shown to inhibit the inflammasome, protected renal function specifically in females and restrained cyst enlargement in both male and female RC/RC mice. Collectively, these results provide evidence for the first time that the activated Caspase-1/inflammasome promotes cyst expansion and disease progression in PKD, particularly in females. Moreover, the data suggest that this innate immune pathway may be a relevant target for therapy in PKD.

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Section: Resultssupporting

confidence: 93%

Caspase-1 and the inflammasome promote polycystic kidney disease progression

Swenson-Fields

Ward

Lopez

et al. 2022

Front. Mol. Biosci.

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“…Proinflammatory cytokines such as IL-1β, TNF-alpha, and IL-2 are present in the cyst microenvironment of human ADPKD kidneys (Gardner et al, 1991), and macrophages accumulate in cystic areas of the kidney (Karihaloo et al, 2011). High expression of interstitial miR-214-3p and its host lncRNA Dnm3os, derived from stromal cells rather than cyst epithelial cells, were validated by both in situ hybridization and single-cell RNA-Seq (Lakhia et al, 2020).…”

Section: Micrornas Play a Role In Inflammationmentioning

confidence: 99%

Non-coding RNAs as potential biomarkers and therapeutic targets in polycystic kidney disease

Zheng

Reid²,

Eccles³

et al. 2022

Front. Physiol.

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Polycystic kidney disease (PKD) is a significant cause of end-stage kidney failure and there are few effective drugs for treating this inherited condition. Numerous aberrantly expressed non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), may contribute to PKD pathogenesis by participating in multiple intracellular and intercellular functions through post-transcriptional regulation of protein-encoding genes. Insights into the mechanisms of miRNAs and other ncRNAs in the development of PKD may provide novel therapeutic strategies. In this review, we discuss the current knowledge about the roles of dysregulated miRNAs and other ncRNAs in PKD. These roles involve multiple aspects of cellular function including mitochondrial metabolism, proliferation, cell death, fibrosis and cell-to-cell communication. We also summarize the potential application of miRNAs as biomarkers or therapeutic targets in PKD, and briefly describe strategies to overcome the challenges of delivering RNA to the kidney, providing a better understanding of the fundamental advances in utilizing miRNAs and other non-coding RNAs to treat PKD.

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Inflammatory Mediators in the Progression of Renal Cystic Disease

Cited by 2 publications

References 9 publications

Caspase-1 and the inflammasome promote polycystic kidney disease progression

Caspase-1 and the inflammasome promote polycystic kidney disease progression

Non-coding RNAs as potential biomarkers and therapeutic targets in polycystic kidney disease

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