Loss of NLRP6 increases the severity of kidney fibrosis
While NLRP3 contributes to kidney fibrosis, the function of most NOD‐likereceptors (NLRs) in chronic kidney disease (CKD) remains unexplored. Toidentify further NLR members involved in the pathogenesis of CKD, wesearched for NLR genes expressed by normal kidneys and differentiallyexpressed in human...
| Autores: | , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad Autónoma de Madrid |
| Repositorio: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.uam.es:10486/713615 |
| Acceso en línea: | http://hdl.handle.net/10486/713615 https://dx.doi.org/10.1002/jcp.31347 |
| Access Level: | acceso abierto |
| Palabra clave: | Chronic Kidney Disease Fibrosis Inflammasome Inflammation NLRP3 NLRP6 Farmacia Medicina |
| Sumario: | While NLRP3 contributes to kidney fibrosis, the function of most NOD‐likereceptors (NLRs) in chronic kidney disease (CKD) remains unexplored. Toidentify further NLR members involved in the pathogenesis of CKD, wesearched for NLR genes expressed by normal kidneys and differentiallyexpressed in human CKD transcriptomics databases. For NLRP6, lower kidneyexpression correlated with decreasing glomerular filtration rate. The role andmolecular mechanisms of Nlrp6 in kidney fibrosis were explored in wild‐typeand Nlrp6‐deficient mice and cell cultures. Data mining of single‐celltranscriptomics databases identified proximal tubular cells as the main site ofNlrp6 expression in normal human kidneys and tubular cell Nlrp6 was lost inCKD. We confirmed kidney Nlrp6 downregulation following murine unilateralureteral obstruction. Nlrp6‐deficient mice had higher kidney p38 MAPKactivation and more severe kidney inflammation and fibrosis. Similar resultswere obtained in adenine‐induced kidney fibrosis. Mechanistically, profibroticcytokines transforming growth factor beta 1 (TGF‐β1) and TWEAK decreasedNlrp6 expression in cultured tubular cells, and Nlrp6 downregulation resulted inincreased TGF‐β1 and CTGF expression through p38 MAPK activation, as wellas in downregulation of the antifibrotic factor Klotho, suggesting that loss ofNlrp6 promotes maladaptive tubular cell responses. The pattern of geneexpression following Nlrp6 targeting in cultured proximal tubular cells wasconsistent with maladaptive transitions for proximal tubular cells described insingle‐cell transcriptomics datasets. In conclusion, endogenous constitutiveNlrp6 dampens sterile kidney inflammation and fibrosis. Loss of Nlrp6expression by tubular cells may contribute to CKD progression |
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