Abstract
Aristolochic acid nephropathy (AAN), as a rapidly progressive interstitial nephropathy due to excessive ingestion of aristolochia herbal medications, has recently raised considerable concerns among clinicians and researchers as its underlying pathogenic mechanisms are largely unclear. In the current study, we identified NLRP3 inflammasome activation as a novel pathological mechanism of AAN. We found that NLRP3 inflammasome was aberrantly activated both in vivo and in vitro after AA exposure. Blockade of IL-1β and NLRP3 inflammasome activation by IL-1Ra significantly attenuated renal tubular injury and function loss in AA-induced nephropathy. Moreover, NLRP3 or Caspase-1 deficiency protected against renal injury in the mouse model of acute AAN, suggesting that the NLRP3 signaling pathway was probably involved in the pathogenesis of AAN. We also found that administration of IL-22 could markedly attenuate renal tubular injury in AAN. Notably, IL-22 intervention significantly alleviated renal fibrosis and dysfunction in AA-induced nephropathy. Furthermore, IL-22 largely inhibited renal activation of NLRP3 inflammasome in AA-induced nephropathy. These results indicated that IL-22 ameliorated renal tubular injury in AAN through suppression of NLRP3 inflammasome activation. In summary, this study identified renal activation of NLRP3 inflammasome as a novel mechanism underlying the pathogenesis of AAN, thus providing a potential therapeutic strategy for AAN based on suppression of NLRP3 inflammasome activation.
Highlights
Aristolochic acid nephropathy (AAN), characterized pathologically by acute tubular injury and clinically by irreversible renal function deterioration, is a progressive tubulointerstitial nephritis that will lead to end-stage renal disease (ESRD) and urothelial malignancy if uncontrolled [1,2,3]
We demonstrated that NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) or Caspase1 deficiency ameliorated renal tubular injury in a murine model of AAN, identifying renal NLRP3 inflammasome activation as a crucial mediator in the pathogenesis of AA-induced nephropathy
On the basis of elucidating a possible association between the activation of NLRP3 inflammasome and the pathogenesis of AAN, we demonstrated for the first time that administration of IL-22 could attenuate renal tubular lesion and function loss in AAN through inhibition of renal activation of NLRP3 inflammasome
Summary
Aristolochic acid nephropathy (AAN), characterized pathologically by acute tubular injury and clinically by irreversible renal function deterioration, is a progressive tubulointerstitial nephritis that will lead to end-stage renal disease (ESRD) and urothelial malignancy if uncontrolled [1,2,3]. It has been indicated that renal activation of the NLRP3 inflammasome occurred in infiltrating immunocytes, primarily including macrophages and dendritic cells, and in some intrinsic renal cells such as kidney tubular epithelial cells. Renal tubular epithelial cells have intensively been demonstrated to express the components of the NLRP3 inflammasome [9,10,11,12]. There is growing evidence that renal NLRP3 inflammasome activation contributes to tubular cell damage in acute kidney injury [13, 14]. Despite numerous literatures demonstrating a detrimental role of NLRP3 inflammasome in experimental renal injury, whether the activation of NLRP3 inflammasome is associated with the progression of AAN remains largely undetermined. The role of NLRP3 signaling pathway in the development and progression of ANN have not been previously described
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