FP250
LOSS OF NLRP6 EXPRESSION INCREASES THE SEVERITY OF ACUTE KIDNEY INJURY Free

INTRODUCTION: Nlrp6 is a nucleotide-binding oligomerization domain-like receptor (NLR) that forms atypical inflammasomes. Nlrp6 modulates the gut epithelium interaction with the microbiota. However, the expression and function of Nlrp6 in the kidney, a sterile environment, have not been characterized. We have explored the role of Nlrp6 in acute kidney injury (AKI).

METHODS: To assess the functional implications of NLRP6 in kidney disease, Nlrp6 knockout mice were studied. Immunohistochemistry, Western blot and RT-PCR was performed in  murine nephrotoxic AKI induced by a folic acid overdose or cisplatin. Nlrp6 expression was determined by immunohistochemistry in human renal biopsies. Nlrp6 function was explored in cultured tubular cells by siRNA knock-down of Nlrp6.

RESULTS: In a transcriptomics array of murine nephrotoxic AKI, Nlrp6 and Naip3 were the only significantly downregulated NLR genes. Nlrp6 was expressed by healthy murine and human kidney tubular epithelium, and expression was reduced during human kidney injury or murine nephrotoxic AKI induced by cisplatin or a folic acid overdose. Genetic Nlrp6 deficiency resulted in upregulation of kidney ERK1/2 and p38 MAP kinase phosphorylation and more severe AKI and kidney inflammation. In cultured tubular cells, Nlrp6 downregulation induced by specific siRNA resulted in upregulation of ERK1/2 and p38 phosphorylation and chemokine mRNA expression and downregulation of the nephroprotective gene Klotho. MAP kinase inhibition prevented the inflammatory response in Nlrp6-deficient cells.

CONCLUSIONS: In conclusion, Nlrp6 dampens sterile inflammation and has a nephroprotective role during nephrotoxic kidney injury through suppression of MAP kinase activation.