The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway

Kapetanaki, Stefania; Kumawat, Ashok Kumar; Persson, Katarina; Demirel, Isak

doi:10.3390/ijms222111864

Cited by 37 publications

(33 citation statements)

References 74 publications

(95 reference statements)

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“…The aberrant activation and proliferation of fibroblasts are thought to be a key cause of renal fibrosis. Evidence exists that the inhibition of PERK-Akt-mTOR-NLRP3 signaling inhibits the renal fibroblast activation and fibroblast proliferation [ 81 ]. In addition to this, NF- κ B translocation and ROS production in renal thylakoid cells exposed to angiotensin II activate NLRP3 inflammasomes, which can lead to glomerular fibrosis [ 82 ].…”

Section: The Role Of the Abnormal Metabolite-induced Nlrp3 Inflammaso...mentioning

confidence: 99%

Metabolic Dysfunction in the Regulation of the NLRP3 Inflammasome Activation: A Potential Target for Diabetic Nephropathy

Zhao

Zhou

Novák

et al. 2022

Journal of Diabetes Research

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Metabolic dysfunction plays a key role in the development of diabetic nephropathy (DN). However, the exact effects and mechanisms are still unclear. The pyrin domain-containing protein 3 (NLRP3) inflammasome, a member of the nod-like receptor family, is considered a crucial inflammatory regulator and plays important roles in the progress of DN. A growing body of evidence suggests that high glucose, high fat, or other metabolite disorders can abnormally activate the NLRP3 inflammasome. Thus, in this review, we discuss the potential function of abnormal metabolites such as saturated fatty acids (SFAs), cholesterol crystals, uric acid (UA), and homocysteine in the NLRP3 inflammasome activation and explain the potential function of metabolic dysfunction regulation of NLRP3 activation in the progress of DN via regulation of inflammatory response and renal interstitial fibrosis (RIF). In addition, the potential mechanisms of metabolism-related drugs, such as metformin and sodium glucose cotransporter (SGLT2) inhibitors, which have served as the suppressors of the NLRP3 inflammasomes, in DN, are also discussed. A better understanding of NLRP3 inflammasome activation in abnormal metabolic microenvironment may provide new insights for the prevention and treatment of DN.

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Section: The Role Of the Abnormal Metabolite-induced Nlrp3 Inflammaso...mentioning

confidence: 99%

Metabolic Dysfunction in the Regulation of the NLRP3 Inflammasome Activation: A Potential Target for Diabetic Nephropathy

Zhao

Zhou

Novák

et al. 2022

Journal of Diabetes Research

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“…NLRP3-mediated damage and necrosis of ECs were also found in diseases which are relevant to vasculopathy [ 14 , 15 ]. NLRP3 also shows ability to activate fibroblasts, the most important cellular component of fibrosis, in chronic inflammatory diseases, inducing cell activation and differentiation [ 16 , 17 ].…”

Section: Overview Of Nlrp3mentioning

confidence: 99%

Role of NLRP3 inflammasome in systemic sclerosis

et al. 2022

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Systemic sclerosis (SSc) is an autoimmune rheumatic disease with high mortality, which is featured by inflammation, vascular damage, and aggressive fibrosis. To date, the pathogenesis of SSc remains unclear and effective treatments are still under research. Active NLRP3 recruits downstream proteins such as ASC and caspase-1 and assembles into inflammasome, resulting in excretion of inflammatory cytokines including IL-1β and IL-18, as well as in pyroptosis mediated by gasdermin D. Various studies demonstrated that NLRP3 inflammasome might be involved in the mechanism of tenosynovitis, arthritis, fibrosis, and vascular damage. The pathophysiological changes might be due to the activation of proinflammatory Th2 cells, profibrotic M2 macrophages, B cells, fibroblasts, and endothelial cells. Here, we review the studies focused on NLRP3 inflammasome activation, its association with innate and adaptive immune cells, endothelium injury, and differentiation of fibroblasts in SSc. Furthermore, we summarize the prospect of therapy targeting NLRP3 pathway.

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“…It consists of tubular cells, peritubular endothelium of the capillaries, extracellular matrix, pericytes, fibroblasts and immune cells [ 16 ]. The role of TMAO in the renal tubulointerstitium has also been a subject of investigation [ 5 , 17 ]. Increased TMAO in a CKD mice model was associated with tubulointerstitial fibrosis [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Increased TMAO in a CKD mice model was associated with tubulointerstitial fibrosis [ 5 ]. We have previously shown that TMAO induces proliferation of human renal fibroblasts and collagen production via the Akt/mTOR pathway [ 17 ]. Tubulointerstitial fibrosis and inflammation lead, in the context of CKD, to nephron loss and progressively declined GFR [ 15 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

TMAO Suppresses Megalin Expression and Albumin Uptake in Human Proximal Tubular Cells Via PI3K and ERK Signaling

Kapetanaki

Kumawat

Persson

et al. 2022

IJMS

Self Cite

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Trimethylamine-N-oxide (TMAO) is a uremic toxin, which has been associated with chronic kidney disease (CKD). Renal tubular epithelial cells play a central role in the pathophysiology of CKD. Megalin is an albumin-binding surface receptor on tubular epithelial cells, which is indispensable for urine protein reabsorption. To date, no studies have investigated the effect of TMAO on megalin expression and the functional properties of human tubular epithelial cells. The aim of this study was first to identify the functional effect of TMAO on human renal proximal tubular cells and second, to unravel the effects of TMAO on megalin-cubilin receptor expression. We found through global gene expression analysis that TMAO was associated with kidney disease. The microarray analysis also showed that megalin expression was suppressed by TMAO, which was also validated at the gene and protein level. High glucose and TMAO was shown to downregulate megalin expression and albumin uptake similarly. We also found that TMAO suppressed megalin expression via PI3K and ERK signaling. Furthermore, we showed that candesartan, dapagliflozin and enalaprilat counteracted the suppressive effect of TMAO on megalin expression. Our results may further help us unravel the role of TMAO in CKD development and to identify new therapeutic targets to counteract TMAOs effects.

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The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway

Cited by 37 publications

References 74 publications

Metabolic Dysfunction in the Regulation of the NLRP3 Inflammasome Activation: A Potential Target for Diabetic Nephropathy

Metabolic Dysfunction in the Regulation of the NLRP3 Inflammasome Activation: A Potential Target for Diabetic Nephropathy

Role of NLRP3 inflammasome in systemic sclerosis

TMAO Suppresses Megalin Expression and Albumin Uptake in Human Proximal Tubular Cells Via PI3K and ERK Signaling

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