Albumin overload triggered NLRP3 inflammasome activation and tubulointerstitial inflammation in tubular epithelial cells through megalin/cubilin receptor-mediated endocytosis and lysosomal rupture.
Does albumin overload induce tubulointerstitial inflammation via megalin/cubilin-mediated lysosome rupture and NLRP3 inflammasome activation in tubular cells?
Megalin/cubilin and lysosome rupture are involved in albumin-triggered tubular injury and tubulointerstitial inflammation, suggesting active control of albuminuria is critical to halt CKD progression.
Albuminuria contributes to the development and progression of chronic kidney disease by inducing tubulointerstitial inflammation (TI) and fibrosis. However, the exact mechanisms of TI in response to albuminuria are unresolved. We previously demonstrated that NLRP3 and inflammasomes mediate albumin-induced lesions in tubular cells. Here, we further investigated the role of endocytic receptors and lysosome rupture in NLRP3 inflammasome activation. A murine proteinuric nephropathy model was induced by albumin overload as described previously. The priming and activation signals for inflammasome complex formation were evoked simultaneously by albumin excess in tubular epithelial cells. The former signal was dependent on a albumin-triggered NF-κB pathway activation. This process is mediated by the endocytic receptor, megalin and cubilin. However, the silencing of megalin or cubilin inhibited the albumin-induced NLRP3 signal. Notably, subsequent lysosome rupture and the corresponding release of lysosomal hydrolases, especially cathepsin B, were observed in tubular epithelial cells exposed to albumin. Cathepsin B release and distribution are essential for NLRP3 signal activation, and inhibitors of cathepsin B suppressed the NLRP3 signal in tubular epithelial cells. Taken together, our findings suggest that megalin/cubilin and lysosome rupture are involved in albumin-triggered tubular injury and TI. This study provides novel insights into albuminuria-induced TI and implicates the active control of albuminuria as a critical strategy to halt the progression of chronic kidney disease.
Liu et al. (Sat,) conducted a other in Proteinuric nephropathy (n=18). Albumin overload vs. Saline was evaluated on NLRP3 inflammasome activation and tubulointerstitial inflammation. Albumin overload triggered NLRP3 inflammasome activation and tubulointerstitial inflammation in tubular epithelial cells through megalin/cubilin receptor-mediated endocytosis and lysosomal rupture.