Megalin/Cubulin-Lysosome-mediated Albumin Reabsorption Is Involved in the Tubular Cell Activation of NLRP3 Inflammasome and Tubulointerstitial Inflammation

Liú, Dan; Wen, Yi; Tang, Tao-Tao; Lv, Lin‐Li; Tang, Ri‐Ning; Liu, Hong; Ma, Kun-Ling; Crowley, Steve D; Liu, Bi‐Cheng

doi:10.1074/jbc.m115.662064

Cited by 90 publications

(45 citation statements)

References 44 publications

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“…reported that albumin overload in PTECs induced a slight increase in megalin and cubilin protein expression at 24 hours, with a marked decrease at 48 hours. The decline was associated with the presence of albumin-induced apoptosis 30 . In human podocytes, we found no such decline in either cubilin or megalin mRNAs and proteins, probably due to the absence of any increase in cell death.…”

Section: Discussionmentioning

confidence: 93%

Albumin uptake in human podocytes: a possible role for the cubilin-amnionless (CUBAM) complex

Gianesello

Priante

Ceol

et al. 2017

Sci Rep

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Albumin re-uptake is a receptor-mediated pathway located in renal proximal tubuli. There is increasing evidence of glomerular protein handling by podocytes, but little is known about the mechanism behind this process. In this study, we found that human podocytes in vitro are committed to internalizing albumin through a receptor-mediated mechanism even after exposure to low doses of albumin. We show that these cells express cubilin, megalin, ClC-5, amnionless and Dab2, which are partners in the tubular machinery. Exposing human podocytes to albumin overload prompted an increase in CUBILIN, AMNIONLESS and CLCN5 gene expression. Inhibiting cubilin led to a reduction in albumin uptake, highlighting its importance in this mechanism. We demonstrated that human podocytes are committed to performing endocytosis via a receptor-mediated mechanism even in the presence of low doses of albumin. We also disclosed that protein overload first acts on the expression of the cubilin-amnionless (CUBAM) complex in these cells, then involves the ClC-5 channel, providing the first evidence for a possible role of the CUBAM complex in albumin endocytosis in human podocytes.

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Section: Discussionmentioning

confidence: 93%

Albumin uptake in human podocytes: a possible role for the cubilin-amnionless (CUBAM) complex

Gianesello

Priante

Ceol

et al. 2017

Sci Rep

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“…In several prior studies, NLRP3 can clearly be seen at tubules in human tissue but the relevance of NLRP3 tubular localization has never been addressed by the authors 21 32 . Furthermore, a recent study by Liu’s group demonstrated NLRP3 expression at tubules in albumin overloaded rats 33 . We found that NLRP3 predominantly localized to the tubules with virtually no staining in glomeruli in histologically normal kidney.…”

Section: Discussionmentioning

confidence: 98%

NLRP3 Localizes to the Tubular Epithelium in Human Kidney and Correlates With Outcome in IgA Nephropathy

Chun

Chung

Wang

et al. 2016

Sci Rep

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Nod-like receptor pyrin domain-containing-3 (NLRP3) has been implicated in the pathogenesis of experimental renal injury, yet its characterization in human kidney disease remains largely unexplored. NLRP3 expression was evaluated in human kidney biopsies, primary renal tubular cells (HPTC) and correlated to disease outcomes in patients with IgA nephropathy (IgAN). NLRP3 localized to renal tubules in normal human kidney tissue and to mitochondria within HPTC by immunohistochemistry and immunofluorescence microscopy. Compared to control kidneys, NLRP3 gene expression was increased in biopsies of patients with IgAN. While NLRP3 expression in IgAN was detected in glomeruli, it remained largely confined to the tubular epithelial compartment. In vitro NLRP3 mRNA and protein expression were transiently induced in HPTC by TGF-β1 but subsequently diminished over time as cells lost their epithelial phenotype in a process regulated by transcription and ubiquitin-mediated degradation. Consistent with the in vitro data, low NLRP3 mRNA expression in kidney biopsies was associated with a linear trend of higher risk of composite endpoint of doubling serum creatinine and end stage renal disease in patients with IgAN. Taken together, these data show that NLRP3 is primarily a kidney tubule-expressed protein that decreases in abundance in progressive IgAN.

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“…Recent studies have indicated that the NLRP3 inflammasome contributes to albumin-induced lesions in tubular cells [38,39]. Liu et al [40] demonstrated that endocytic receptor-lysosome-mediated albumin reabsorption was involved in the tubular cell activation of NLRP3 inflammasome and tubulointerstitial inflammation. Moreover, studies from Zhuang et al reported that NLRP3 inflammasome mediated albumin-induced renal tubular injury through impaired mitochondrial function [41] and further provided direct evidence indicating the important role of the albumin-NLRP3 inflammasome axis in mediating the impairment of renal tubular tight junctions and integrity [42].…”

Section: Nlrs and Ckdmentioning

confidence: 99%

The Nucleotide Oligomerization Domain-Like Receptors in Kidney Injury

Wang

2016

Kidney Dis

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Background: Inflammation is a hallmark of almost all forms of renal injury and the activation of the innate immune system is of importance in the development of many kidney diseases. Pattern recognition receptors (PRRs) act as sensors of the innate immune system to detect pathogen- or damage-associated molecular patterns, which initiate immune responses to resolve infections and repair damaged tissues. Abnormalities in PRR activation will lead to excessive inflammation. Summary: Nucleotide oligomerization domain (NOD)-like receptors (NLRs) are recently identified intracellular PRRs that are essential to innate immune responses and tissue homeostasis. A better understanding of the function of NLRs will provide unexpected opportunities to develop new therapies for kidney diseases by modulation of the innate immune system. Key Messages: NLRs are constitutively expressed in the kidney and emerging evidence has shown that activation of NLRs plays an important role in the pathogenesis of renal injury. Among NLRs, NOD2 and NLRP3 inflammasome are the best characterized members in the kidney. In this review, we summarize current knowledge about the pathological mechanisms that are related to NOD2 and NLRP3 inflammasome in various kidney diseases by their canonical and non-canonical effects and discuss the opportunities of pharmacological targeting of NLR-mediated signaling pathways at multiple levels for the treatment of renal disease.

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Megalin/Cubulin-Lysosome-mediated Albumin Reabsorption Is Involved in the Tubular Cell Activation of NLRP3 Inflammasome and Tubulointerstitial Inflammation

Cited by 90 publications

References 44 publications

Albumin uptake in human podocytes: a possible role for the cubilin-amnionless (CUBAM) complex

Albumin uptake in human podocytes: a possible role for the cubilin-amnionless (CUBAM) complex

NLRP3 Localizes to the Tubular Epithelium in Human Kidney and Correlates With Outcome in IgA Nephropathy

The Nucleotide Oligomerization Domain-Like Receptors in Kidney Injury

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