title: Megalin/Cubulin-Lysosome-mediated Albumin Reabsorption Is Involved in the Tubular Cell Activation of NLRP3 Inflammasome and Tubulointerstitial Inflammation.
abstract: 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.
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing 210009, Jiangsu, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing 210009, Jiangsu, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing 210009, Jiangsu, China.
authors.forename: Tao-Tao
authors.initials: TT
authors.lastname: Tang
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing 210009, Jiangsu, China.
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Lv
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing 210009, Jiangsu, China.
authors.forename: Ri-Ning
authors.initials: RN
authors.lastname: Tang
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing 210009, Jiangsu, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing 210009, Jiangsu, China.
authors.forename: Kun-Ling
authors.initials: KL
authors.lastname: Ma
authors.affiliation: Department of Medicine, Division of Nephrology, Duke University, and Durham Veterans Affairs Medical Centers, Durham, North Carolina 27710.
authors.forename: Steve D
authors.initials: SD
authors.lastname: Crowley
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing 210009, Jiangsu, China. Electronic address: liubc64@163.com.
authors.forename: Bi-Cheng
authors.initials: BC
authors.lastname: Liu
mesh_terms: D000419:Albuminuria / Q000150:complications / Q000276:immunology* / Q000473:pathology; D000818:Animals; D002352:Carrier Proteins / Q000276:immunology*; D002401:Cathepsin B / Q000276:immunology; D002460:Cell Line; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D020382:Interleukin-18 / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D007674:Kidney Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology; D007684:Kidney Tubules / Q000276:immunology / Q000473:pathology*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000276:immunology*; D008247:Lysosomes / Q000276:immunology / Q000473:pathology; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000276:immunology*; D012709:Serum Albumin / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D011956:Receptors, Cell Surface; D012709:Serum Albumin; C029486:intrinsic factor-cobalamin receptor; D002401:Cathepsin B
keywords: NLRP3; cathepsin B (CTSB); epithelial cell; lysosome; proteinuria