Nlrp6: un componente Nefroprotector del inflamasoma

Resumen

NLRP6 is a recently described and poorly characterized member of the (NOD)-Like Receptor (NLR) family. NLRP6 is the only NLR member to date that is able to form the classical and the non-classical inflammasome and negatively regulate the NF-B and MAPK inflammatory pathways. NLRP6 is highly expressed in gut epithelial cells where it appears to play a protective role, regulating the interaction with microbiota. However, the expression and function of NLRP6 in the kidney, a sterile environment, have not been characterized yet. We have explored the role of NLRP6 in acute kidney injury (AKI). By transcriptomic analysis of murine nephrotoxic AKI, we found that Nlrp6 is the NLR family gene most expressed in healthy kidneys and the most significantly downregulated during experimental AKI. NLRP6 was expressed by healthy murine and human kidney tubular epithelium, and its expression was reduced during human kidney injury or murine nephrotoxic AKI induced by cisplatin or by a folic acid overdose. Genetic Nlrp6 deficiency in vivo resulted in phosphorylation of kidney ERK1/2 and p38 MAP kinases and more severe AKI and kidney inflammation. In cultured murine tubular cells, Nlrp6 downregulation induced by specific siRNAs resulted in upregulation of ERK1/2 and p38 phosphorylation, chemokine mRNA expression and downregulation of the nephroprotective gene Klotho. MAPK inhibition prevented the inflammatory response in Nlrp6-deficient cells. The role of NLRP6 in the pathogenesis of chronic kidney disease (CKD) was also characterized. We searched the human transcriptomics Nephroseq database for NLR genes differentially expressed in progressive human CKD. NLRP6 mRNA stood out as decreased in CKD kidney and low NLRP6 mRNA expression correlated with decreased estimated glomerular filtration rate (eGFR). The role of NLRP6 in kidney fibrosis was explored in an accelerated model of CKD, unilateral ureteral obstruction (UUO). Genetic Nlrp6 deficiency in vivo resulted in an upregulation of kidney p38 MAP kinase phosphorylation, upregulation of extracellular matrix-related gene expressions and more severe kidney inflammation after UUO. In vitro, the profibrotic factor TGF-β1 caused Nlrp6 mRNA downregulation. We also evaluated the impact of kidney disease on NLRP6 expression in other organs. During experimental AKI induced by cisplatin or folic acid and in human samples from patients with CKD, we observed that NLRP6 expression was downregulated in the colon as a consequence of kidney damage. In conclusion, in a sterile environment, NLRP6 has a nephroprotective role, dampening inflammatory and fibrotic responses, probably by preventing MAPK activation. Our results also demonstrate the existence of a kidney damage-gut axis in which gut NLRP6 is downregulated during kidney injury. Upregulation of NLRP6 expression may be explored as therapeutic option in kidney disease.