Uremic toxins induce kidney fibrosis by activating intrarenal renin–angiotensin–aldosterone system associated epithelial-to-mesenchymal transition Original paper

What was studied

This study investigated how the microbiome-derived uremic toxins indoxyl sulfate (IS) and p-cresol sulfate (PCS) contribute to kidney fibrosis by stimulating the renal renin–angiotensin–aldosterone system-associated epithelial-to-mesenchymal transition. The research examined whether these toxins—generated from gut microbial protein fermentation—activate intrarenal RAAS signaling, upregulate TGF-β/Smad pathways, and trigger EMT-like changes that drive fibrotic remodeling in chronic kidney disease. The authors also tested whether the angiotensin receptor blocker (ARB) losartan could mitigate these toxin-driven effects. Molecular analyses in cultured renal tubular cells and half-nephrectomized mice provide a mechanistic map linking microbiome-derived toxins to progressive renal injury.

Who was studied

The study used mouse proximal renal tubular cell lines (PKSV-PRs) and ten-week-old half-nephrectomized B6 mice. Cells were treated with graded concentrations of IS or PCS for 72 hours, while animals received daily intraperitoneal IS or PCS for four weeks. Additional groups received oral losartan to evaluate pathway inhibition. Across both models, the investigators analyzed RAAS components, TGF-β signaling, EMT-related transcription factors, and histologic fibrosis, creating a comprehensive picture of toxin-induced renal injury.

Most important findings

IS and PCS robustly activated the intrarenal RAAS. Both toxins increased renin, angiotensinogen, and AT1 receptor expression while suppressing the protective AT2 receptor in vitro and in vivo. Angiotensin II levels rose markedly, confirming pathway activation. Downstream, IS and PCS increased TGF-β1 secretion, heightened Smad2, Smad3, and Smad4 signaling, and significantly upregulated the EMT-associated transcription factor Snail, as confirmed by western blot and nuclear immunostaining (page 4 images). These changes coincided with hallmark EMT features: increased fibronectin and α-SMA and reduced E-cadherin, visible in stained sections of mouse kidneys (page 5 images). Chronic toxin exposure led to severe interstitial and glomerular fibrosis, while losartan markedly reduced TGF-β1 and Snail expression and diminished nephrosclerosis scores.

The table below summarizes four major microbial-toxin–linked mechanisms reported.

Key implications

This study provides direct mechanistic evidence that microbiome-derived uremic toxins—specifically IS and PCS—activate a pathological RAAS/TGF-β/EMT axis within the kidney. These findings strengthen the concept that dysbiosis-related toxin accumulation is not merely a biomarker of CKD severity but a driver of structural kidney damage. Clinically, this supports targeting microbial toxin production, enhancing gut barrier integrity, modifying microbial metabolism, or using RAAS blockade to slow CKD progression. The study also positions EMT-associated markers—Snail, fibronectin, α-SMA, and E-cadherin loss—as potential components of a microbiome-linked kidney fibrosis signature useful for integrative biomarker frameworks.

Citation

Sun CY, Chang SC, Wu MS. Uremic toxins induce kidney fibrosis by activating intrarenal renin–angiotensin–aldosterone system associated epithelial-to-mesenchymal transition. PLoS One. 2012;7(3):e34026. doi:10.1371/journal.pone.0034026