The interplay between microbiota‐dependent metabolite trimethylamine N‐oxide, Transforming growth factor β/SMAD signaling and inflammasome activation in chronic kidney disease patients: A new mechanistic perspective

• Published in: Journal of cellular biochemistry Vol. 120; no. 9; pp. 14476 - 14485
• Main Authors: El‐Deeb, Omnia Safwat, Atef, Marwa Mohamed, Hafez, Yasser Mostafa
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2019
• Subjects: Activation; Biomarkers; Chronic kidney disease; Fibrosis; Growth factors; IL‐1β; Inflammasomes; Interleukins; Kidney diseases; Kidneys; Leucine; Metabolites; Microbiota; mRNA; NLRP3; Nucleotides; Oligomerization; Oxidative stress; Pathogenesis; Polymerase chain reaction; Pyrin protein; Signaling; Smad protein; SMAD3; Smad3 protein; Structure-function relationships; TGF‐β1 and TMAO; Toxins; Transforming growth factor; Transforming growth factor-b; Transforming growth factor-b1; Trimethylamine; TGF-β1 and TMAO; NLRP3; Chronic kidney disease; SMAD3; IL-1β
• ISSN: 0730-2312; 1097-4644; 1097-4644
• DOI: 10.1002/jcb.28707

Background Chronic kidney disease (CKD) signifies a frequently life‐threatening condition influencing kidney structure and function. Despite its irrefutable importance, its exact pathogenesis is not completely clarified. However, CKD is known to be associated with accumulated uremic toxins/metabolites, interstitial fibrosis, and systemic inflammation. So we aimed to investigate the role of microbiota‐dependent metabolite trimethylamine N‐oxide (TMAO), transforming growth factor β (TGFβ)/SMAD signaling, and inflammasome activation in CKD pathogenesis through its different stages. Subjects and Methods Eighty patients with CKD of stages 2 to 4 in addition 15 healthy control subjects were enrolled. SMAD3 and nucleotide‐binding oligomerization domain‐, leucine‐rich repeat‐ and pyrin domain‐containing 3 (NLRP3) messenger RNA (mRNA) expressions from whole blood were assessed by quantitative real‐time polymerase chain reaction (RT‐PCR). Serum TGF‐β1 and interleukin‐1β (IL‐1β) levels were estimated by the enzyme‐linked immunosorbent assay. Plasma and urinary TMAO levels were measured. Oxidative stress markers were also assessed. Results SMAD3 and NLRP3 mRNA expressions were significantly upregulated in patients with CKD. Likewise, serum TGF‐β1 and IL‐1β levels were significantly elevated in patients with CKD, with increase in plasma and urinary TMAO levels and altered redox status throughout different CKD stages. Conclusion The study documented that TMAO could be used as a reliable biomarker to evaluate CKD progression; being linked to TGF‐β/SMAD signaling, NLRP3 inflammasome activation as well as being a noninvasive applicable technique. A better understanding of the CKD pathogenesis helps clinicians to optimize proper diagnosis and management. The turbulences of gut microbiome is recognized in CKD and proposed to be a crucial factor in CKD pathogenesis. This study found a significant correlation between TMAO level and TGFβ/SMAD signaling in CKD progression. TMAO is also linked to NLRP3 inflammosome initiation and redox status in CKD progression through its different stages. Thus TMAO level can be used as noninvasive biomarker to mirror the CKD progression.