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Nox1-derived oxidative stress as a common pathogenic link between obesity and hyperoxaluria-related kidney injury

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Abstract

Specific relationships among reactive oxygen species, activation pathways, and inflammatory mechanisms involved in kidney injury were assessed in a combined model of obesity and hyperoxaluria. Male Wistar rats were divided into four groups: Control, HFD (high fat diet), OX (0.75% ethylene glycol), and HFD + OX (combined model) Changes in basal O2− levels were evaluated by chemiluminescence in renal interlobar arteries and renal cortex. Furthermore, the effect of different inhibitors on NADPH-stimulated O2− generation was assessed in renal cortex. Oxidative stress sources, and local inflammatory mediators, were also determined, in parallel, by RT-PCR, and correlated with measures of renal function, urinary biochemistry, and renal structure. Rats from the HFD group developed overweight without lipid profile alteration. Tubular deposits of crystals were seen in OX and severely enhanced in HFD + OX groups along with a significantly higher impairment of renal function. Basal oxidative stress was increased in renal cortex of OX rats and in renal arteries of HFD rats, while animals from the combined HFD + OX group exhibited the highest levels of oxidative stress in renal cortex, derived from xanthine oxidase and COX-2. NADPH oxidase-dependent O2− generation was elevated in renal cortex of the OX group and markedly enhanced in the HFD + OX rats, and associated to an up-regulation of Nox1 and a down-regulation of Nox4 expression. High levels of oxidative stress in the kidney, of OX and HFD + OX groups were also associated to an inflammatory response mediated by an elevation of TNFα, COX-2, NFκB1 MCP-1, and OPN. Oxidative stress is a key pathogenic factor in renal disease associated to hyperoxaluria and a common link underlying the exacerbated inflammatory response and kidney injury found under conditions of both obesity and hyperoxaluria. Nox1 pathway must be considered as a potential therapeutic target.

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Data availability statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CaOx:

Calcium oxalate

COX:

Cyclooxygenase

CRD:

Chronic renal disease

EG:

Ethylene glycol

HFD:

High fat diet

MCP:

Monocyte chemoattractant protein

NADPH:

Nicotinamide adenine dinucleotide phosphate

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NO:

Nitric oxide

Nox:

NADPH oxidase enzymes

O2− :

Superoxide

OPN:

Osteopontin

ROS:

Reactive oxygen species

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Funding

Spanish Urological Foundation. The Spanish Urological Association funded this study. AEU Research Grant 2017 and Grant SAF2016-77526-R from the Spanish Ministry of Economy and Competitivity.

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Author notes

  1. D. Prieto and J. Carballido authors equally contributed to this work.

Authors and Affiliations

  1. Department of Urology, Hospital Universitario Puerta de Hierro-Majadahonda, Universidad Rey Juan Carlos, Calle Manuel de Falla, 1, Majadahonda, 28222, Madrid, Spain

    J. Sáenz-Medina

  2. Department of Physiology, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain

    M. Muñoz, A. Sanchez, C. Rodriguez & D. Prieto

  3. Department of Clinical Biochemistry, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain

    E. Jorge, E. Donoso & E. Virumbrales

  4. Department of Pathology, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain

    C. Corbacho & D. Izquierdo

  5. Medical and Surgical Research Facility, Instituto de Investigación Sanitaria Puerta de Hierro, Madrid, Spain

    M. Santos

  6. Biobank, Instituto de Investigación Sanitaria Puerta de Hierro, Madrid, Spain

    A. Sanchez

  7. Molecular Biology and DNA Sequencing Facility, Instituto de Investigación Sanitaria Puerta de Hierro, Madrid, Spain

    E. Ramil

  8. Confocal Microscopy Facility, Instituto de Investigación Sanitaria Puerta de Hierro, Madrid, Spain

    M. J. Coronado

  9. Department of Urology, Hospital Universitario Puerta de Hierro-Majadahonda, Universidad Autónoma de Madrid, Madrid, Spain

    J. Carballido

Authors
  1. J. Sáenz-Medina
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  2. M. Muñoz
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  3. A. Sanchez
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  5. E. Jorge
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  9. E. Donoso
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  10. E. Virumbrales
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  11. A. Sanchez
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Correspondence to J. Sáenz-Medina.

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Sáenz-Medina, J., Muñoz, M., Sanchez, A. et al. Nox1-derived oxidative stress as a common pathogenic link between obesity and hyperoxaluria-related kidney injury . Urolithiasis 48, 481–492 (2020). https://doi.org/10.1007/s00240-019-01170-w

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  • DOI: https://doi.org/10.1007/s00240-019-01170-w

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