NLRC5,　as　the　largest　member　of　nucleotide-binding　domain　and　leucine-rich　repeat　(NLR)　family,　was　involved　in　various　physiological　processes,　such　as　inflammation,　fibrosis,　innate　immunity　and　diabetic　nephropathy.　However,　the　role　of　NLRC5　in　acute　kidney　injury　remains　unclear.　The　aim　of　this　study　was　to　investigate　the　role　of　NLRC5　in　human　renal　proximal　tubular　epithelial　cells　(HK-2)　exposed　to　hypoxia/reoxygenation　(H/R).　Our　results　demonstrated　that　the　expression　of　NLRC5　was　significantly　up-regulated　in　HK-2　cells　exposed　to　H/R.　Knockdown　of　NLRC5　significantly　improved　the　viability　of　HK-2　cells　exposed　to　H/R.　In　addition,　knockdown　of　NLRC5　efficiently　inhibited　H/R-induced　oxidative　stress　and　apoptosis　in　HK-2　cells.　Mechanistically,　knockdown　of　NLRC5　markedly　enhanced　the　activation　of　PIK3/Akt　signaling　pathway　in　H/R-stimulated　HK-2　cells.　In　summary,　our　findings　indicate　that　knockdown　of　NLRC5　attenuates　renal　I/R　injury　in　vitro　through　the　activation　of　PI3K/Akt　signaling　pathway.