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Urolithiasis

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

  • J. Sáenz-MedinaEmail author
  • M. Muñoz
  • A. Sanchez
  • C. Rodriguez
  • E. Jorge
  • C. Corbacho
  • D. Izquierdo
  • M. Santos
  • E. Donoso
  • E. Virumbrales
  • A. Sanchez
  • E. Ramil
  • M. J. Coronado
  • D. Prieto
  • J. Carballido
Original Paper
  • 5 Downloads

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.

Keywords

Obesity Oxidative stress Urolithiasis NADPH oxidase Renal injury 

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

Notes

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

240_2019_1170_MOESM1_ESM.docx (12 kb)
Supplementary material 1 (DOCX 11 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • J. Sáenz-Medina
    • 1
    Email author
  • M. Muñoz
    • 2
  • A. Sanchez
    • 2
  • C. Rodriguez
    • 2
  • E. Jorge
    • 3
  • C. Corbacho
    • 4
  • D. Izquierdo
    • 4
  • M. Santos
    • 5
  • E. Donoso
    • 3
  • E. Virumbrales
    • 3
  • A. Sanchez
    • 6
  • E. Ramil
    • 7
  • M. J. Coronado
    • 8
  • D. Prieto
    • 2
  • J. Carballido
    • 9
  1. 1.Department of Urology, Hospital Universitario Puerta de Hierro-MajadahondaUniversidad Rey Juan CarlosMadridSpain
  2. 2.Department of Physiology, Facultad de FarmaciaUniversidad Complutense de MadridMadridSpain
  3. 3.Department of Clinical BiochemistryHospital Universitario Puerta de Hierro-MajadahondaMadridSpain
  4. 4.Department of PathologyHospital Universitario Puerta de Hierro-MajadahondaMadridSpain
  5. 5.Medical and Surgical Research FacilityInstituto de Investigación Sanitaria Puerta de HierroMadridSpain
  6. 6.BiobankInstituto de Investigación Sanitaria Puerta de HierroMadridSpain
  7. 7.Molecular Biology and DNA Sequencing FacilityInstituto de Investigación Sanitaria Puerta de HierroMadridSpain
  8. 8.Confocal Microscopy FacilityInstituto de Investigación Sanitaria Puerta de HierroMadridSpain
  9. 9.Department of Urology, Hospital Universitario Puerta de Hierro-MajadahondaUniversidad Autónoma de MadridMadridSpain

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