Abstract
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.
Highlights
IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis in the world[14]
We have demonstrated for the first time a relationship between NLRP3 expression and human disease progression in IgAN
Using a combination of in vitro studies in human proximal tubular cells with clinical correlation to human kidney biopsy samples from patients with IgAN, we have established that NLRP3 is primarily expressed in the kidney tubular epithelium in humans with reduced expression at the transcription and post-translational level during tubular injury in vitro and in vivo
Summary
IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis in the world[14]. Studies have demonstrated NLRP3 expression in tubular epithelial cells as well as podocytes that plays an important role in experimental disease pathogenesis[3,7,10,20,21] These data suggest that the biology of the NLRP3 in the kidney may differ from the canonical inflammasome pathway described in macrophages and other non-renal disease models that rely primarily caspase-1 activation and cytokine maturation[22]. Despite these observations, the cellular localization and characterization of NLRP3 in the human kidney or a temporal relationship to human kidney disease has yet to be confirmed. In this extension of our prior work, we employed human nephrectomy samples, kidney disease biopsies and primary tubular epithelial cells to characterize NLRP3 in the context of the human kidney and IgAN, a common chronic human kidney disease
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