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A biologic- and chemical-induced rat model of glomerular and tubular injury

ABSTRACT: Nonsurgical rodent chronic kidney disease (CKD) models for both glomerular and tubular injuries are currently limited. This study aimed to develop a rat model of CKD by combining anti-Fx1A with N(ω)-nitrophenyl-L-arginine methyl ester (L-NAME) administration. The rats were assigned to groups receiving L-NAME, anti-Fx1A, anti-Fx1A + L-NAME, or vehicle. Renal function, stiffness, injury biomarkers, histopathology and genome-wide transcriptomic changes were evaluated. Protein and renal injury biomarker levels in the urine were elevated in the anti-Fx1A alone and combination groups. Shear wave elastography revealed increased stiffness of the kidneys in all treatment groups. Histopathological evaluation revealed glomerular injury, characterized by enlarged glomeruli with increased hyaline materials in both anti-Fx1A groups and tubular degeneration/regeneration in the renal cortex of all treated groups, with the highest incidence and severity in the combination group. These tubular changes were sometimes accompanied by interstitial mononuclear cell infiltrates and interstitial fibrosis. Proteinuria and mild changes in blood, urine renal injury biomarkers and imaging endpoints were noted in association with these histopathologic changes. The concurrence and higher incidence and/or severity of glomerular and tubular injuries in the combination group indicate that this would be a useful and relevant CKD model suitable for mechanistic, pharmacologic and toxicological investigations.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE283627 | GEO | 2024/12/06

REPOSITORIES: GEO

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Project description:Background: Short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, are produced by gut microbiota through fermentation of complex carbohydrates that cannot be digested by the human host. They affect gut health and can contribute at the distal level to the pathophysiology of several diseases, including renal pathologies. Methods: SCFA levels were measured in chronic kidney disease (CKD) patients (n = 54) at different stages of the disease and associations with renal function and inflammation parameters were examined. The impact of propionate and butyrate in pathways triggered in tubular cells under inflammatory conditions was analysed using genome-wide expression assays. Finally, a pre-clinical mouse model of folic acid-induced transition from acute kidney injury to CKD was used to analyse the preventive and therapeutic potential of these microbial metabolites in the development of CKD. Results: Faecal levels of propionate and butyrate in CKD patients gradually reduce as the disease progresses, and do so in close association with established clinical parameters for serum creatinine, blood urea nitrogen and the estimated glomerular filtration rate. Propionate and butyrate jointly downregulated the expression of 103 genes related to inflammatory processes and immune system activation triggered by TNF-α in tubular cells. In vivo, the administration of propionate and butyrate, either before or soon after injury, respectively prevented and slowed the progression of damage. This was indicated by a decrease in renal injury markers, the expression of pro-inflammatory and pro-fibrotic markers, and recovery of renal function over the long term. Conclusions: Propionate and butyrate levels are associated with a progressive loss of renal function in CKD patients. Early administration of these SCFAs prevents disease advancement in a pre-clinical model of acute renal damage, demonstrating their therapeutic potential independently of the gut microbiota.

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A biologic- and chemical-induced rat model of glomerular and tubular injury

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