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This research was funded by by a 2017 AEU research grant from the Spanish Urological Association and PID2019-105689RB. Ministerio de Ciencia e Innovacion (Spain) co-funded by the FEDER program of the EU.

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Hyperoxaluria Induces Endothelial Dysfunction in Preglomerular Arteries: Involvement of Oxidative Stress

Publicated to:Cells. 11 (15): - 2022-08-01 11(15), DOI: 10.3390/cells11152306

Authors: Saenz-Medina, Javier; Munoz, Mercedes; Rodriguez, Claudia; Contreras, Cristina; Sanchez, Ana; Jose Coronado, Maria; Ramil, Elvira; Santos, Martin; Carballido, Joaquin; Prieto, Dolores;

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Abstract

Urolithiasis is a worldwide problem and a risk factor for kidney injury. Oxidative stress-associated renal endothelial dysfunction secondary to urolithiasis could be a key pathogenic factor, similar to obesity and diabetes-related nephropathy. The aim of the present study was to characterize urolithiasis-related endothelial dysfunction in a hyperoxaluria rat model of renal lithiasis. Experimental approach: Endothelial dysfunction was assessed in preglomerular arteries isolated from control rats and in which 0.75% ethylene glycol was administered in drinking water. Renal interlobar arteries were mounted in microvascular myographs for functional studies; superoxide generation was measured by chemiluminescence and mRNA and protein expression by RT-PCR and immunofluorescence, respectively. Selective inhibitors were used to study the influence of the different ROS sources, xanthine oxidase, COX-2, Nox1, Nox2 and Nox4. Inflammatory vascular response was also studied by measuring the RNAm expression of NF-kappa B, MCP-1 and TNF alpha by RT-PCR. Results: Endothelium-dependent vasodilator responses were impaired in the preglomerular arteries of the hyperoxaluric group along with higher superoxide generation in the renal cortex and vascular inflammation developed by MCP-1 and promoted by NF-kappa B. The xanthine oxidase inhibitor allopurinol restored the endothelial relaxations and returned superoxide generation to basal values. Nox1 and Nox2 mRNA were up-regulated in arteries from the hyperoxaluric group, and Nox1 and Nox2 selective inhibitors also restored the impaired vasodilator responses and normalized NADPH oxidase-dependent higher superoxide values of renal cortex from the hyperoxaluric group. Conclusions: The current data support that hyperoxaluria induces oxidative stress-mediated endothelial dysfunction and inflammatory response in renal preglomerular arteries which is promoted by the xanthine oxidase, Nox1 and Nox2 pathways.

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