Abstract
Indoxyl sulfate is a uremic toxin and a ligand of the aryl-hydrocarbon receptor (AhR), a transcriptional regulator. Elevated serum indoxyl sulfate levels may contribute to progressive kidney disease and associated vascular disease. We asked whether indoxyl sulfate injures podocytes in vivo and in vitro. Mice exposed to indoxyl sulfate for 8 w exhibited prominent tubulointerstitial lesions with vascular damage. Indoxyl sulfate-exposed mice with microalbuminuria showed ischemic changes, while more severely affected mice showed increased mesangial matrix, segmental solidification, and mesangiolysis. In normal mouse kidneys, AhR was predominantly localized to the podocyte nuclei. In mice exposed to indoxyl sulfate for 2 h, isolated glomeruli manifested increased Cyp1a1 expression, indicating AhR activation. After 8 w of indoxyl sulfate, podocytes showed foot process effacement, cytoplasmic vacuoles, and a focal granular and wrinkled pattern of podocin and synaptopodin expression. Furthermore, vimentin and AhR expression in the glomerulus was increased in the indoxyl sulfate-exposed glomeruli compared to controls. Glomerular expression of characteristic podocyte mRNAs was decreased, including Actn4, Cd2ap, Myh9, Nphs1, Nphs2, Podxl, Synpo, and Wt1. In vitro, immortalized-mouse podocytes exhibited AhR nuclear translocation beginning 30 min after 1 mM indoxyl sulfate exposure, and there was increased phospho-Rac1/Cdc42 at 2 h. After exposure to indoxyl sulfate for 24 h, mouse podocytes exhibited a pro-inflammatory phenotype, perturbed actin cytoskeleton, decreased expression of podocyte-specific genes, and decreased cell viability. In immortalized human podocytes, indoxyl sulfate treatment caused cell injury, decreased mRNA expression of podocyte-specific proteins, as well as integrins, collagens, cytoskeletal proteins, and bone morphogenetic proteins, and increased cytokine and chemokine expression. We propose that basal levels of AhR activity regulate podocyte function under normal conditions, and that increased activation of podocyte AhR by indoxyl sulfate contributes to progressive glomerular injury.
Highlights
Numerous factors likely contribute to the progression of chronic kidney disease (CKD), including the primary disease process, the effects of systemic hypertension, proteinuria, and filtered cytokines; glomerular hypertension and hyperfiltration through remnant nephrons; and the effect of various uremic toxins, which are many [1]
These findings suggest that the uremic toxin indoxyl sulfate, acting via aryl-hydrocarbon receptor (AhR), may contribute to the progression of glomerular injury in CKD
Previous studies have shown that AhRs localize to the renal and collecting tubules of human fetal kidneys [42], as well as to podocytes in fetal and adult mouse kidneys [21]
Summary
Numerous factors likely contribute to the progression of chronic kidney disease (CKD), including the primary disease process, the effects of systemic hypertension, proteinuria, and filtered cytokines; glomerular hypertension and hyperfiltration through remnant nephrons; and the effect of various uremic toxins, which are many [1]. Indoxyl sulfate is of particular interest as it has been implicated in both CKD progression and a range of manifestations of CKD, including cardiovascular disease, endothelial dysfunction, bone disease, and genomic damage [2,3,4,5]. Total serum indoxyl sulfate levels are ,2 mM (,0.5 mg/L) in healthy controls and average approximately 150 mM (30 mg/L) in uremia, including CKD stage 5 and dialysis [1,13]. Rat studies suggested that elevated serum indoxyl sulfate exacerbates glomerulosclerosis and tubulointerstitial lesions [11,12,14]. Indoxyl sulfate localizes to tubular cells, into which it is transported by organic anion transporters, and podocytes in uremic rats [15]
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