Kongsintaweesuk, Suppakrit, Tunbenjasiri, Keerapach, Pongking, Thatsanapong, Roytrakul, Sitiruk, Charoenlappanit, Sawanya, Anutrakulchai, Sirirat, Pairojkul, Chawalit, Intuyod, Kitti, Tanasuka, Pakornkiat, Blair, David, Pinlaor, Somchai, and Pinlaor, Porntip (2025) Microcystin-LR exacerbates chronic kidney disease in rats: insights into gut microbiome and host proteome dysregulation. Life Sciences, 378. 123840.

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Abstract

Aims: This study aimed to investigate the effects of microcystin-leucine arginine (MC-LR), an environmental nephrotoxin, on the gut-kidney axis in chronic kidney disease (CKD), focusing on interactions between the gut microbiome and host proteome. Materials and methods: Male Sprague-Dawley rats were administered adenine (200 mg/kg/day) for 10 days to induce kidney injury, followed by MC-LR (10 μg/mL/kg, i.p., every other day for 4 weeks). Renal function (Blood urea nitrogen, BUN; Serum creatinine, SCr and urine albumin to creatinine ratio, uACR) and kidney pathology (EGTI histology scores and picrosirius-red staining) were assessed. Expression of kidney injury (KIM-1), fibrosis (CTGF), inflammation (HMGB1 and CD3), oxidative stress (H2AX) markers were evaluated by immunohistochemical staining. Gut microbiota was analyzed by 16S rRNA sequencing, and fecal proteomics by LC-MS/MS. Key findings: MC-LR markedly exacerbated adenine-induced kidney injury, leading to impair kidney function (elevated BUN, SCr, and uACR levels) and worsen kidney histopathology (higher EGTI histology scores and prominent fibrosis). Elevated expression levels of KIM1, HMBG1, CTGF, H2AX and CD3 were observed following MC-LR exposure. Notably, pro-inflammatory bacterial families (Enterococcaceae, Enterobacteriaceae) were elevated, while beneficial taxa (Bifidobacteriaceae, Muribaculaceae) decreased in the combination group. Proteomic analysis revealed upregulation of inflammatory markers (TXNIP, Itgb3bp), which correlated with Enterococcaceae abundance. Bifidobacteriaceae negatively correlated with kidney injury markers. Significance: Our study reveals that MC-LR exacerbates chronic kidney disease progression by disrupting the gut-kidney axis. We highlight gut barrier integrity and inflammation as crucial therapeutic targets, offering novel insights and intervention strategies for CKD management, particularly in beyond early stages.

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