title: Albumin impairs renal tubular tight junctions via targeting the NLRP3 inflammasome.
abstract: Proteinuria is, not only a hallmark of glomerular disease, but also a contributor to kidney injury. However, its pathogenic mechanism is still elusive. In the present study, the effects of albumin on renal tubular tight junctions and the potential molecular mechanisms of those effects were investigated. In mouse proximal tubular cells (mPTCs), albumin treatment resulted in a significant loss of the cellular tight junction proteins zonula occludens-1 (ZO-1) and claudin-1 in a time- and dose-dependent manner, indicating a severe impairment of the tight junctions. On the basis of our previous study showing that albumin stimulated NLRP3 [neuronal apoptosis inhibitor protein, major histocompatibility complex class 2 transcription activator, incompatibility locus protein from Podospora anserina, and telomerase-associated protein (NACHT); leucine-rich repeat (LRR); and pyrin domain (PYD) domains-containing protein 3] inflammasome activation in mPTCs, we pretreated mPTCs with NLRP3 siRNA (siNLRP3) and found that NLRP3 knockdown significantly blocked the downregulation of ZO-1 and claudin-1 induced by albumin. Similarly, in albumin-overloaded wild-type mice, both ZO-1 and claudin-1 were downregulated at the protein and mRNA levels in parallel with the impaired formation of the tight junctions on transmission electron microscopy and the abnormal renal tubular morphology on periodic acid-Schiff staining, which contrasted with the stimulation of NLRP3 in the renal tubules. In contrast, NLRP3 knockout (NLRP3(-/-)) mice preserved normal ZO-1 and claudin-1 expression as well as largely normal tight junctions and tubular morphology. More importantly, deletion of the NLRP3 pathway downstream component caspase-1 similarly blocked the albumin overload-induced downregulation of ZO-1 and claudin-1. Taken together, these findings demonstrated an important role of the albumin-NLRP3 inflammasome axis in mediating the impairment of renal tubular tight junctions and integrity.
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing, China; Department of Pediatrics, The First People's Hospital of Changzhou, Changzhou, China.
authors.forename: Yibo
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing, China;
authors.forename: Caiyu
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing, China;
authors.forename: Guixia
authors.initials: G
authors.lastname: Ding
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing, China;
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing, China;
authors.forename: Songming
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing, China;
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing, China; zhaihua@njmu.edu.cn.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000419:Albuminuria / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D062445:Claudin-1 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010539:Permeability; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D012710:Serum Albumin, Bovine; D019108:Tight Junctions / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D013997:Time Factors; D014162:Transfection; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D012333:RNA, Messenger; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D012710:Serum Albumin, Bovine; D020170:Caspase 1
keywords: albumin; claudin-1; tight junction; zonula occludens-1