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Lactobacillus salivarius BP121 prevents cisplatin?induced acute kidney injury by inhibition of uremic toxins such as indoxyl sulfate and p?cresol sulfate via alleviating dysbiosis.

ABSTRACT: The gut microbiota is important for maintaining the integrity of the intestinal barrier, promoting immunological tolerance and carrying out metabolic activities that have not evolved in hosts. Intestinal dysbiosis is associated with chronic kidney disease and probiotic supplementation has been shown to be beneficial. However, it is not known whether gut microorganisms?specifically, lactic acid bacteria (LAB) can protect against acute kidney injury (AKI). To address this issue, the present study investigated the effects of Lactobacillus salivarius BP121, an intestinal LAB isolated from the feces of newborns, in a rat model of cisplatin?induced AKI and also in Caco?2 human intestinal epithelial cells. BP121 prevented cisplatin?induced AKI in rats, as demonstrated by decreases in inflammation and oxidative stress in kidney tissue and in serum levels of uremic toxins such as indoxyl sulfate (IS) and p?cresol sulfate (PCS). BP121 also reduced intestinal permeability, as determined using fluorescein isothiocyanate?dextran by immunohistochemical detection of tight junction (TJ) proteins such as zona occludens?1 and occludin. The abundance of Lactobacillus spp., which are beneficial intestinal flora, was increased by BP121; this was accompanied by an increase in the concentrations of short?chain fatty acids in feces. Additionally, H2O2?induced TJ protein damage was reduced in Caco?2 cells treated with BP121 culture supernatant, an effect that was reversed by the 5' AMP?activated protein kinase (AMPK) inhibitor Compound C and Toll?like receptor (TLR)4 inhibitor TLR4?IN?C34. In conclusion, this study demonstrated that L. salivarius BP121 protects against cisplatin?induced AKI by decreasing inflammation and oxidative stress and this renoprotective effect is partially mediated by modulating the gut environment and thereby suppressing IS and PCS production as well as by regulating AMPK and TLR4 dependent TJ assembly.

SUBMITTER: Lee TH

PROVIDER: S-EPMC7053870 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Lactobacillus salivarius BP121 prevents cisplatin‑induced acute kidney injury by inhibition of uremic toxins such as indoxyl sulfate and p‑cresol sulfate via alleviating dysbiosis.

Lee Tae-Hee TH Park Dongsun D Kim Yang Ji YJ Lee Isaac I Kim Suae S Oh Chang-Taek CT Kim Joem-Yong JY Yang Jihyun J Jo Sang-Kyung SK

International journal of molecular medicine 20200210 4

The gut microbiota is important for maintaining the integrity of the intestinal barrier, promoting immunological tolerance and carrying out metabolic activities that have not evolved in hosts. Intestinal dysbiosis is associated with chronic kidney disease and probiotic supplementation has been shown to be beneficial. However, it is not known whether gut microorganisms‑specifically, lactic acid bacteria (LAB) can protect against acute kidney injury (AKI). To address this issue, the present study ...[more]

PMID: 32124946

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Project description:Indoxyl sulfate is a uremic toxin and a ligand of the aryl-hydrocarbon receptor (AhR), a transcriptional regulator. Elevated serum indoxyl sulfate levels may contribute to progressive kidney disease and associated vascular disease. We asked whether indoxyl sulfate injures podocytes in vivo and in vitro. Mice exposed to indoxyl sulfate for 8 w exhibited prominent tubulointerstitial lesions with vascular damage. Indoxyl sulfate-exposed mice with microalbuminuria showed ischemic changes, while more severely affected mice showed increased mesangial matrix, segmental solidification, and mesangiolysis. In normal mouse kidneys, AhR was predominantly localized to the podocyte nuclei. In mice exposed to indoxyl sulfate for 2 h, isolated glomeruli manifested increased Cyp1a1 expression, indicating AhR activation. After 8 w of indoxyl sulfate, podocytes showed foot process effacement, cytoplasmic vacuoles, and a focal granular and wrinkled pattern of podocin and synaptopodin expression. Furthermore, vimentin and AhR expression in the glomerulus was increased in the indoxyl sulfate-exposed glomeruli compared to controls. Glomerular expression of characteristic podocyte mRNAs was decreased, including Actn4, Cd2ap, Myh9, Nphs1, Nphs2, Podxl, Synpo, and Wt1. In vitro, immortalized-mouse podocytes exhibited AhR nuclear translocation beginning 30 min after 1 mM indoxyl sulfate exposure, and there was increased phospho-Rac1/Cdc42 at 2 h. After exposure to indoxyl sulfate for 24 h, mouse podocytes exhibited a pro-inflammatory phenotype, perturbed actin cytoskeleton, decreased expression of podocyte-specific genes, and decreased cell viability. In immortalized human podocytes, indoxyl sulfate treatment caused cell injury, decreased mRNA expression of podocyte-specific proteins, as well as integrins, collagens, cytoskeletal proteins, and bone morphogenetic proteins, and increased cytokine and chemokine expression. We propose that basal levels of AhR activity regulate podocyte function under normal conditions, and that increased activation of podocyte AhR by indoxyl sulfate contributes to progressive glomerular injury.

Dataset Information

Lactobacillus salivarius BP121 prevents cisplatin?induced acute kidney injury by inhibition of uremic toxins such as indoxyl sulfate and p?cresol sulfate via alleviating dysbiosis.

Publications

Lactobacillus salivarius BP121 prevents cisplatin‑induced acute kidney injury by inhibition of uremic toxins such as indoxyl sulfate and p‑cresol sulfate via alleviating dysbiosis.

Similar Datasets

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