Carvacrol preserves antioxidant status and attenuates kidney fibrosis <i>via</i> modulation of TGF-β1/Smad signaling and inflammation

Ram, Chetan; Gairola, Shobhit; Syed, Abu Mohammad; Verma, Shobhit; Mugale, Madhav Nilakanth; Sahu, Bidya Dhar

doi:10.1039/d2fo01384c

Cited by 11 publications

(2 citation statements)

References 47 publications

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“…Besides the above molecules involved in fibrosis, reactive oxygen species (ROS) overproduction induced by UUO can promote inflammation, oxidative stress, and apoptosis, which contributes to fibrosis [36,37]. In this paper, we found a deficiency in the antioxidant capacity of UUO or CIN kidney, previous research found UUO induction resulted in impaired renal function along with the downregulation of antioxidant proteins, such as NRF2, NQO1 and SOD, as a result, more ROS produced finally leads to oxidative stress and fibrosis [38,39]. While the expression of SOD2, an antioxidant enzyme, can protect against chronic kidney injury and renal fibrosis by reducing oxidative stress in renal tubular cells [40,41].…”

Section: Discussionmentioning

confidence: 83%

Single cell multi-omics of fibrotic kidney reveal epigenetic regulation of antioxidation and apoptosis within proximal tubule

Chen,

Ye,

Zhu

et al. 2024

Cell. Mol. Life Sci.

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Background Until now, there has been no particularly effective treatment for chronic kidney disease (CKD). Fibrosis is a common pathological change that exist in CKD. Methods To better understand the transcriptional dynamics in fibrotic kidney, we make use of single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) and single-cell RNA sequencing (scRNA-seq) from GEO datasets and perform scRNA-seq of human biopsy to seek possible transcription factors (TFs) regulating target genes in the progress of kidney fibrosis across mouse and human kidneys. Results Our analysis has displayed chromatin accessibility, gene expression pattern and cell–cell communications at single-cell level in kidneys suffering from unilateral ureteral obstruction (UUO) or chronic interstitial nephritis (CIN). Using multimodal data, there exists epigenetic regulation producing less Sod1 and Sod2 mRNA within the proximal tubule which is hard to withstand oxidative stress during fibrosis. Meanwhile, a transcription factor Nfix promoting the apoptosis-related gene Ifi27 expression found by multimodal data was validated by an in vitro study. And the gene Ifi27 upregulated by in situ AAV injection within the kidney cortex aggravates kidney fibrosis. Conclusions In conclusion, as we know oxidation and apoptosis are traumatic factors during fibrosis, thus enhancing antioxidation and inhibiting the Nfix-Ifi27 pathway to inhibit apoptosis could be a potential treatment for kidney fibrosis.

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Section: Discussionmentioning

confidence: 83%

Single cell multi-omics of fibrotic kidney reveal epigenetic regulation of antioxidation and apoptosis within proximal tubule

Chen,

Ye,

Zhu

et al. 2024

Cell. Mol. Life Sci.

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“…The canonical arm of the TGF-β pathway functions through adaptor proteins (Smad2, Smad3, and Smad4). TGF-β initiates the phosphorylation cascade of these proteins, forming a trimeric complex that migrates to the nucleus and transcribes various fibrotic genes [37]. Elevated expression of TGF-β and downstream signaling components have been reported in patients and murine DN models [8,38].…”

Section: Discussionmentioning

confidence: 99%

Biochanin A Ameliorates Nephropathy in High-Fat Diet/Streptozotocin-Induced Diabetic Rats: Effects on NF-kB/NLRP3 Axis, Pyroptosis, and Fibrosis

et al. 2023

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Nephropathy is the most prevalent microvascular disorder in diabetes mellitus. Oxidative stress and inflammatory cascade provoked by the persistent hyperglycemic milieu play integral roles in the aggravation of renal injury and fibrosis. We explored the impact of biochanin A (BCA), an isoflavonoid, on the inflammatory response, nod-like receptor protein 3 (NLRP3) inflammasome activation, oxidative stress, and fibrosis in diabetic kidneys. A high-fat-diet/streptozotocin (HFD/STZ)-induced experimental model of diabetic nephropathy (DN) was established in Sprague Dawley rats, and in vitro studies were performed in high-glucose-induced renal tubular epithelial (NRK-52E) cells. Persistent hyperglycemia in diabetic rats was manifested by perturbation of renal function, marked histological alterations, and oxidative and inflammatory renal damage. Therapeutic intervention of BCA mitigated histological changes, improved renal function and antioxidant capacity, and suppressed phosphorylation of nuclear factor-kappa B (NF-κB) and nuclear factor-kappa B inhibitor alpha (IκBα) proteins. Our in vitro data reveal excessive superoxide generation, apoptosis, and altered mitochondrial membrane potential in NRK-52E cells that were cultured in a high-glucose (HG) environment were subsided by BCA intervention. Meanwhile, the upregulated expressions of NLRP3 and its associated proteins, the pyroptosis-indicative protein gasdermin-D (GSDMD) in the kidneys, and HG-stimulated NRK-52E cells were significantly ameliorated by BCA treatment. Additionally, BCA blunted transforming growth factor (TGF)-β/Smad signaling and production of collagen I, collagen III, fibronectin, and alfa-smooth muscle actin (α-SMA) in diabetic kidneys. Our results indicate the plausible role of BCA in attenuating DN, presumably through modulation of the apoptotic cascade in renal tubular epithelial cells and the NF-κB/NLRP3 axis.

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Sorafenib and edaravone protect against renal fibrosis induced by unilateral ureteral obstruction via inhibition of oxidative stress, inflammation, and RIPK-3/MLKL pathway

Abou Taha,

Ali,

Saleh

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Renal fibrosis is the common endpoint of nearly all chronic and progressive nephropathies. Cell death and sterile inflammation are the main characteristics of renal fibrosis, which can lead to end-stage renal failure. The inflammatory reaction triggered by tissue damage is strongly related to necroptosis, a type of caspase-independent, regulated cell death. Using an animal model of unilateral ureteral obstruction (UUO), the anti-fibrotic effects of sorafenib (SOF), a multi-kinase inhibitor, and edaravone (EDV), a potent antioxidant and free radical scavenger, were examined in rats with obstructive nephropathy. Experimentally, animals were divided randomly into five groups: sham; UUO; UUO + SOF (5 mg/kg/day, P.O.); UUO + EDV (20 mg/kg/day, P.O.); and UUO + SOF + EDV groups. The kidney function biomarkers, oxidant/antioxidant status, renal mRNA expressions of TNF-α, collagen-1α, protein expressions of RIPK-1, RIPK-3, MLKL, caspase-8, HYP, MPO, and TNF-α were all significantly modulated by UUO. Administration of either SOF or EDV significantly attenuated cellular and molecular changes induced by UUO. Also, histopathological changes were improved. Moreover, SOF in combination with EDV, significantly improved UUO-induced renal fibrosis compared with each drug alone. Collectively, administration of either SOF or EDV or both of them significantly attenuated the rats with obstructive nephropathy, possibly by blocking the RIPK-3/MLKL necroptotic pathway and suppressing renal oxidative stress and inflammation.

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Carvacrol preserves antioxidant status and attenuates kidney fibrosis via modulation of TGF-β1/Smad signaling and inflammation

Abstract: Chronic kidney disease (CKD) with diverse aetiologies is emerging as a challenging kidney disorder associated with inflammation and interstitial fibrosis. Carvacrol (CVL) is a bioactive monoterpenoid found abundantly in oregano,...

Cited by 11 publications

References 47 publications

Single cell multi-omics of fibrotic kidney reveal epigenetic regulation of antioxidation and apoptosis within proximal tubule

Single cell multi-omics of fibrotic kidney reveal epigenetic regulation of antioxidation and apoptosis within proximal tubule

Biochanin A Ameliorates Nephropathy in High-Fat Diet/Streptozotocin-Induced Diabetic Rats: Effects on NF-kB/NLRP3 Axis, Pyroptosis, and Fibrosis

Sorafenib and edaravone protect against renal fibrosis induced by unilateral ureteral obstruction via inhibition of oxidative stress, inflammation, and RIPK-3/MLKL pathway

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