NLRP3 associated with chronic kidney disease progression after ischemia/reperfusion-induced acute kidney injury

Abstract

Nod-like receptor protein 3 (NLRP3), as an inflammatory regulator, has been implicated in acute kidney injury (AKI). Failed recovery after AKI can lead to chronic kidney disease (CKD). However, the role of NLRP3 in the AKI-CKD transition is still unknown. A mild or severe AKI mouse model was performed by using ischemia-reperfusion injury (IRI). We evaluated the renal NLRP3 expression in acute and chronic phases of ischemic AKI, respectively. Although serum creatinine (Cr) and blood urea nitrogen (BUN) levels in AKI chronic phase were equivalent to normal baseline, histological analysis and fibrotic markers revealed that severe AKI-induced maladaptive tubular repair with immune cell infiltration and fibrosis. Tubular damage was restored completely in mild AKI rather than in severe AKI. Of note, persistent overexpression of NLRP3 was also found in severe AKI but not in mild AKI. In the severe AKI-induced chronic phase, there was a long-term high level of NLRP3 in serum or urine. Overt NLRP3 was mainly distributed in the abnormal tubules surrounded by inflammatory infiltrates and fibrosis, which indicated the maladaptive repair. Renal Nlrp3 overexpression was correlated with infiltrating macrophages and fibrosis. Renal NLRP3 signaling-associated genes were upregulated after severe AKI by RNA-sequencing. Furthermore, NLRP3 was found increased in renal tubular epitheliums from CKD biopsies. Together, persistent NLRP3 overexpression was associated with chronic pathological changes following AKI, which might be a new biomarker for evaluating the possibility of AKI-CKD transition.

Human natural killer cells can activate NLRP1 and NLRP3 inflammasomes and drives pyroptosis

“…Inflammasome activity has been associated to chronic kidney disease and the rejection of the graft in kidney-transplanted patients, particularly linked to AIM-2, NLRP3, and more recently NLRP1 [32][33][34][35][36]. Kidney transplantation is considered the best therapy for patients with end-stage kidney disease, being associated with better quality of life and patient survival compared with dialysis.…”

NLRP3: Role in ischemia/reperfusion injuries

“…Moreover, TLR4-associated increase in the activity of the platelet NLRP3 inflammasome has been reported to promote aggregation of platelets in a mice model of hindlimb ischemia ( 87 ). Similarly, I/R induced-acute kidney injury has been shown to be associated with over-expression of NLRP3 is overexpressed in chronic kidney disease ( 88 ). NLRP3 inflammasome is also implicated in the tissue injury and impairment of spermatogenesis caused by testicular I/R ( 89 ).…”

Metabolic Dysfunction in the Regulation of the NLRP3 Inflammasome Activation: A Potential Target for Diabetic Nephropathy

“…DN undergoes a transition from renal inflammation to fibrosis [ 57 ]. Renal NLRP3 overexpression is associated with macrophage infiltration and fibrosis [ 58 ]. When the microenvironment is altered, the kidney is in an acute kidney injury (AKI) state, and as the first defender, immune cells maintain cellular homeostasis.…”

“…This induces a glomerular injury affecting glomerular endothelial cells, thylakoid cells, and podocytes [ 20 , 59 , 60 ]. When the disease progresses further, dominant NLRP3 is predominantly distributed in abnormal renal tubules surrounded by inflammatory infiltration and fibrosis, and tubular epithelial cells are atrophied and dispersed, indicating maladaptive repair [ 58 ].…”