NLRP3 Localizes to the Tubular Epithelium in Human Kidney and Correlates With Outcome in IgA Nephropathy.
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.
Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Justin
J
Chun
Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Hyunjae
H
Chung
Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Xiangyu
X
Wang
Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Rebecca
R
Barry
Department of Pathology and Laboratory Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Zohreh Mohammad
ZM
Taheri
Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Jaye M
JM
Platnich
Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Sofia B
SB
Ahmed
Department of Pathology and Laboratory Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Kiril
K
Trpkov
Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Brenda
B
Hemmelgarn
Department of Pathology and Laboratory Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Hallgrimur
H
Benediktsson
Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Matthew T
MT
James
Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
Daniel A
DA
Muruve
D000328:Adult; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D005922:Glomerulonephritis, IGA / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality*; D006801:Humans; D007150:Immunohistochemistry; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D054875:Ubiquitination
D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1