Valiño-Rivas L, et al. - Whether and how Nlrp6 (a nucleotide-binding oligomerization domain-like receptor (NLR) that forms atypical inflammasomes) holds significance in acute kidney injury (AKI), was investigated in this study. The only significantly downregulated NLR genes in a transcriptomics array of murine nephrotoxic AKI were Nlrp6 and Naip3. Mice and cultured murine tubular cells were analyzed to determine the functional implications of Nlrp6 downregulation. The presence of Nlrp6 expression in healthy murine and human kidney tubular epithelium was evident, and expression was shown to be decreased during human kidney injury or murine nephrotoxic AKI caused by cisplatin or a folic acid overdose. The consequences of genetic Nlrp6 deficiency included upregulation of kidney extracellular signal–regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) phosphorylation and more severe AKI as well as kidney inflammation. Overall, findings revealed the dampening of sterile inflammation by Nlrp6 as well as a nephroprotective role of Nlrp6 during nephrotoxic kidney injury via suppression of MAP kinase activation.