Abstract
The NOD-like receptor family, pyrin domain containing-3 (NLRP3) inflammasome has been implicated in renal inflammation and fibrosis. However, the biological function of inflammasome-independent NLRP3 in non-immune cells is still unclear. We evaluated the role of inflammasome-independent NLRP3 in renal tubular cells and assessed the value of NLRP3 as a therapeutic target for acute kidney injury (AKI). Various renal tubular cell lines and primary cultured tubular cells from NLRP3 knockout (KO) mice were used for in vitro studies. We also tested the role of tubular NLRP3 in AKI with a unilateral ureter obstruction model (UUO). Hypoxia induced significant increase of NLRP3 independent of ASC, caspase-1, and IL-1β. NLRP3 in renal tubular cells relocalized from the cytosol to the mitochondria during hypoxia and bound to mitochondrial antiviral signal protein (MAVS). The deletion of NLRP3 or MAVS in renal tubular cells attenuated mitochondrial reactive oxygen species (ROS) production and depolarization of the mitochondrial membrane potentials under hypoxia. In response to UUO, NLRP3 KO mice showed less fibrosis, apoptosis, and ROS injury than wild type (WT) mice. Compared with WT kidney, mitophagy was up-regulated in NLRP3 KO kidney relative to the baseline and it was protective against AKI. Our results indicate that inflammasome-independent NLRP3 in renal tubular cells plays important role in mitochondrial ROS production and injury by binding to MAVS after hypoxic injury. This mitochondrial regulation in the absence of NLRP3 increases autophagy and attenuates apoptosis after UUO. We suggest that inflammasome-independent NLRP3 could be a therapeutic target of AKI to prevent the progression of chronic kidney disease.
Highlights
The NOD-like receptor family, pyrin domain-containing-3 (NLRP3) inflammasome is a multiprotein complex and sensor in innate immune cells activated by damage-associated molecular patterns (DAMPs) and it promotes the secretion of pro-inflammatory cytokines such as IL1β and IL-18
These results indicate that NLRP3 expression was increased in renal tubular epithelial cells in hypoxia independent of inflammasome
NLRP3 was present in the mitochondrial fraction under hypoxia in Human kidney-2 (HK-2) cells (Figure 2D)
Summary
The NOD-like receptor family, pyrin domain-containing-3 (NLRP3) inflammasome is a multiprotein complex and sensor in innate immune cells activated by damage-associated molecular patterns (DAMPs) and it promotes the secretion of pro-inflammatory cytokines such as IL1β and IL-18. The relocalization of NLRP3 to the mitochondria and mitochondrial ROS and mitochondrial DNA are the major secondary signals in kidney disease [7, 8]. We previously reported that mitochondrial ROS is crucial for the activation of the NLRP3 inflammasome in macrophages by hyperuricemia in type 2 diabetic nephropathy and the mitochondrially targeted antioxidant, Mito-TEMPO, attenuated NLRP3 increase, and IL-1β release [9]. The role of inflammasome-independent NLRP3 in non-immune cells has been reported to be associated with mitochondrial function. Renal tubular epithelial cells express a considerable amount of inflammasome components such as NLRP3, ASC and caspase-1 but do not produce IL-1β [10]. Inflammasome-independent NLRP3 has been suggested to be related with mitochondrial injury in non-immune cells, the role of inflammasome-independent NLRP3 in kidney disease has not been clarified yet
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