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Caffeic Acid, One of the Major Phenolic Acids of the Medicinal Plant Antirhea borbonica, Reduces Renal Tubulointerstitial Fibrosis.

ABSTRACT: The renal fibrotic process is characterized by a chronic inflammatory state and oxidative stress. Antirhea borbonica (A. borbonica) is a French medicinal plant found in Reunion Island and known for its antioxidant and anti-inflammatory activities mostly related to its high polyphenols content. We investigated whether oral administration of polyphenol-rich extract from A. borbonica could exert in vivo a curative anti-renal fibrosis effect. To this aim, three days after unilateral ureteral obstruction (UUO), mice were daily orally treated either with a non-toxic dose of polyphenol-rich extract from A. borbonica or with caffeic acid (CA) for 5 days. The polyphenol-rich extract from A. borbonica, as well as CA, the predominant phenolic acid of this medicinal plant, exerted a nephroprotective effect through the reduction in the three phases of the fibrotic process: (i) macrophage infiltration, (ii) myofibroblast appearance and (iii) extracellular matrix accumulation. These effects were associated with the mRNA down-regulation of Tgf-β, Tnf-α, Mcp1 and NfkB, as well as the upregulation of Nrf2. Importantly, we observed an increased antioxidant enzyme activity for GPX and Cu/ZnSOD. Last but not least, desorption electrospray ionization-high resolution/mass spectrometry (DESI-HR/MS) imaging allowed us to visualize, for the first time, CA in the kidney tissue. The present study demonstrates that polyphenol-rich extract from A. borbonica significantly improves, in a curative way, renal tubulointerstitial fibrosis progression in the UUO mouse model.

SUBMITTER: Veeren B

PROVIDER: S-EPMC8065974 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Caffeic Acid, One of the Major Phenolic Acids of the Medicinal Plant Antirhea borbonica, Reduces Renal Tubulointerstitial Fibrosis.

Veeren Bryan B Bringart Matthieu M Turpin Chloe C Rondeau Philippe P Planesse Cynthia C Ait-Arsa Imade I Gimié Fanny F Marodon Claude C Meilhac Olivier O Gonthier Marie-Paule MP Diotel Nicolas N Bascands Jean-Loup JL

Biomedicines 20210330 4

The renal fibrotic process is characterized by a chronic inflammatory state and oxidative stress. Antirhea borbonica (A. borbonica) is a French medicinal plant found in Reunion Island and known for its antioxidant and anti-inflammatory activities mostly related to its high polyphenols content. We investigated whether oral administration of polyphenol-rich extract from A. borbonica could exert in vivo a curative anti-renal fibrosis effect. To this aim, three days after unilat ...[more]

PMID: 33808509

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Project description:BackgroundRenal tubulointerstitial fibrosis is the hallmark of various chronic kidney diseases. Symmetric dimethylarginine (SDMA) is an independent cardiovascular risk factor in patients with chronic kidney diseases, which is mostly excreted through renal tubules. However, the effect of SDMA on kidneys in a pathological condition is currently unknown. In this study, we investigated the role of SDMA in renal tubulointerstitial fibrosis and explored its underlying mechanisms.MethodsMouse unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI) models were established to study renal tubulointerstitial fibrosis. SDMA was injected into kidneys through ureter retrogradely. TGF-β stimulated human renal epithelial (HK2) cells were used as an in vitro model and treated with SDMA. Signal transducer and activator of transcription-4 (STAT4) was inhibited by berbamine dihydrochloride or siRNA or overexpressed by plasmids in vitro. Masson staining and Western blotting were performed to evaluate renal fibrosis. Quantitative PCR was performed to validate findings derived from RNA sequencing analysis.ResultsWe observed that SDMA (from 0.01 to 10 µM) dose-dependently inhibited the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells. Intrarenal administration of SDMA (2.5 µmol/kg or 25 µmol/kg) dose-dependently attenuated renal fibrosis in UUO kidneys. A significant increase in SDMA concentration (from 19.5 to 117.7 nmol/g, p < 0.001) in mouse kidneys was observed after renal injection which was assessed by LC-MS/MS. We further showed that intrarenal administration of SDMA attenuated renal fibrosis in UIRI induced mouse fibrotic kidneys. Through RNA sequencing analysis, we found that the expression of STAT4 was reduced by SDMA in UUO kidneys, which was further confirmed by quantitative PCR and Western blotting analysis in mouse fibrotic kidneys and renal cells. Inhibition of STAT4 by berbamine dihydrochloride (0.3 mg/ml or 3.3 mg/ml) or siRNA reduced the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells. Furthermore, blockage of STAT4 attenuated the anti-fibrotic effect of SDMA in TGF-β stimulated HK2 cells. Conversely, overexpression of STAT4 reversed the anti-fibrotic effect of SDMA in TGF-β stimulated HK2 cells.ConclusionTaken together, our study indicates that renal SDMA ameliorates renal tubulointerstitial fibrosis through inhibition of STAT4.

Project description:Background and objectivesUromodulin, produced exclusively in the kidney's thick ascending limb, is a biomarker of kidney tubular health. However, the relationship between urine uromodulin and histologic changes in the kidney tubulointerstitium has not been characterized. In this study, we test the association of urine uromodulin with kidney histologic findings in humans and mice.Design, setting, participants, & measurementsWe investigated the independent association of urine uromodulin measured at the time of kidney biopsy with histologic features in 364 participants at two academic medical centers from 2015 to 2018 using multivariable linear regression models. This relationship was further examined by comparison of uromodulin staining in murine models of kidney fibrosis and repair.ResultsWe found urine uromodulin to be correlated with serum creatinine (rho=-0.43; P<0.001), bicarbonate (0.20; P<0.001), and hemoglobin (0.11; P=0.03) at the time of biopsy but not with urine albumin (-0.07; P=0.34). Multivariable models controlling for prebiopsy GFR, serum creatinine at biopsy, and urine albumin showed higher uromodulin to be associated with lower severity of interstitial fibrosis/tubular atrophy and glomerulosclerosis (interstitial fibrosis/tubular atrophy: -3.5% [95% confidence intervals, -5.7% to -1.2%] and glomerulosclerosis: -3.3% [95% confidence intervals, -5.9% to -0.6%] per two-fold difference in uromodulin). However, when both interstitial fibrosis/tubular atrophy and glomerulosclerosis were included in multivariable analysis, only interstitial fibrosis/tubular atrophy was independently associated with uromodulin (interstitial fibrosis/tubular atrophy: -2.5% [95% confidence intervals, -4.6% to -0.4%] and glomerulosclerosis: -0.9% [95% confidence intervals, -3.4% to 1.5%] per two-fold difference in uromodulin). In mouse kidneys, uromodulin staining was found to be lower in the fibrotic model than in normal or repaired models.ConclusionsHigher urine uromodulin is independently associated with lower tubulointerstitial fibrosis in both human kidney biopsies and a mouse model of fibrosis.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_08_10_CJN04360422.mp3.

Dataset Information

Caffeic Acid, One of the Major Phenolic Acids of the Medicinal Plant Antirhea borbonica, Reduces Renal Tubulointerstitial Fibrosis.

Publications

Caffeic Acid, One of the Major Phenolic Acids of the Medicinal Plant <i>Antirhea borbonica</i>, Reduces Renal Tubulointerstitial Fibrosis.

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