Metabolic syndrome contributes to renal injury mediated by hyperoxaluria in a murine model of nephrolithiasis

Medina, J. Sáenz; Jorge, Eduardo; Corbacho, C.; Santos, Martín; Sánchez, Ana; Soblechero, P.; Virumbrales, E.; Ramil, Elvira; Coronado, María José; Castillón, I.; Prieto, Dolores; Carballido, Joaquı́n

doi:10.1007/s00240-017-0979-9

Cited by 9 publications

(12 citation statements)

References 21 publications

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“…Detectable inflammatory serum markers have been reported in renal stone patients [10], and in diabetic patients with urolithiasis compared to diabetic patients without urolithiasis [22]; the latter supports our recent findings that metabolic disease exacerbates local kidney inflammatory reaction in a rat model of hyperoxaluria [23]. Other studies, however, did not find any significant differences in serum values of inflammatory markers amongst four groups of patients: control, metabolic syndrome, urolithiasis, or both [24], similar to the present study.…”

Section: Discussionsupporting

confidence: 92%

Urolithiasis Develops Endothelial Dysfunction as a Clinical Feature

Medina

Martínez

Rosado³

et al. 2021

Antioxidants

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An increased risk of cardiovascular morbidity has been reported in lithiasic patients. In this context, endothelial dysfunction (ED), an earlier status of atherogenesis, has been identified in hyperoxaluria rat models of urolithiasis. Objective: The purpose of this study was to determine the endothelial vascular function in patients with urolithiasis in relation to systemic inflammatory, oxidative stress, and vascular function serum markers. Methods: A cross-sectional study was performed between 27 urolithiasic patients, matched for age and sex, with 27 healthy patients. Endothelial function was assessed by measuring flow-mediated dilation (Celermajer method). Fasting blood was collected to determine metabolic parameters (glucose and lipid profile), along with serum CRP, IL-6, MDA, ADMA, and VCAM-1. Results: Both the control and urolithiasis groups were homogenous in anthropometric, exploration, and general laboratory measures. Flow-mediated dilation (%FMD) was 11.85% (SE: 2.78) lower in the lithiasis group (p < 0.001). No significant differences were achieved between groups when CRP, IL-6, MDA, ADMA, and VCAM-1 were compared, although slightly higher values of CRP, ADMA, and VCAM-1 were detected in the lithiasic group. A correlation was not reached in any of the serum markers when they were related to flow-mediated values, although a slight negative correlation trend was observed in MDA, VCAM-1, and IL-6 values. Conclusions: Endothelial dysfunction constitutes an important disorder related to urolithiasis patients. It must be considered as an early feature responsible for future cardiovascular events. Our study did not find a significant association between inflammatory, oxidative stress, endothelial serum markers, and flow-mediated dilation.

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Section: Discussionsupporting

confidence: 92%

Urolithiasis Develops Endothelial Dysfunction as a Clinical Feature

Medina

Martínez

Rosado³

et al. 2021

Antioxidants

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“…However, the relationship between inflammation and potential oxidative stress was not analyzed. Moreover, the 65 days of treatment with a 60% fructose diet in their study did not successfully induce MS features other than dyslipidaemia, and thus, their model should not be recognized as a successful MS rat model [ 18 ]. Our previous studies [ 19 , 20 ] also indicated that MS could be induced in ob/ob mice fed normal chow at 28 weeks of age.…”

Section: Discussionmentioning

confidence: 99%

A pilot dynamic analysis of formative factors of nephrolithiasis related to metabolic syndrome: evidence in a rat model

Tang

et al. 2022

Renal Failure

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Introduction and objective To examine the dynamic changes in the formative factors of nephrolithiasis and the final micromorphological changes in an obesity-initiated metabolic syndrome (MS) rat model. Methods Forty five-week-old male Sprague–Dawley (SD) rats were randomly divided into four groups: the regular diet group (RD), high-fat diet group (HFD), regular diet with drug (ethylene glycol and ammonium chloride) group (RDD), and high-fat diet with drug group (HFDD). A dynamic assessment of MS components (body weight (BW), body length (BL), Lee’s index (LI), blood glucose (BG), total cholesterol (TC), and triglycerides (TGs)) and stone-forming factors (urinary pH, urinary calcium, and urinary oxalate acid) was carried out. In addition, the levels of oxidative stress (OS) markers (CAT, SOD, TAC, GSH-PX, and MDA) were measured, and histological analysis was carried out at the end of 16 weeks. Results MS-related parameters, such as BW, LI, BG, TC, and TG, were significantly higher in HFD-fed rats than in RD-fed rats ( p < 0.001). In the HFDD group, significantly lower urinary pH, hyperoxaluria, and hypocalciuria were noted in the dynamic assessment of stone-forming factors ( p < 0.001). CAT, TAC, and MDA were notably changed in the HFD-fed groups, particularly the HFDD rats. Histological analysis showed that the renal tubules of HFDD rats had the highest scores for both inflammation and renal crystallization deposition ( p < 0.05). Conclusions Our results suggest that male SD rats with MS are prone to developing nephrolithiasis. Validation in an in vivo model may lead to an understanding of the underlying pathophysiological mechanisms of action of MS-related nephrolithiasis in humans. Key messages Male SD rats with metabolic syndrome are more prone to developing calcium oxalate nephrolithiasis after treatment with ethylene glycol and ammonium chloride compared to control lean rats. MS-related nephrolithiasis in rats induced by ethylene glycol and ammonium chloride is mainly related to increased hyperoxaluria and inflammation and decreased antioxidant levels. High-fat diet-fed SD rats treated with ethylene glycol and ammonium chloride are a stable and valid in vivo model for understanding the potential mechanism of action of MS-related nephrolithiasis.

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“…Hyperoxaluria model has recently been characterized by our group in previous studies [ 9 , 10 ]. This model develops kidney failure with a significantly lower creatinine clearance compared to the control group, higher percentage of tubules affected by crystal deposits, and interstitial inflammation of the animals affected.…”

Section: Methodsmentioning

confidence: 99%

“…This model develops kidney failure with a significantly lower creatinine clearance compared to the control group, higher percentage of tubules affected by crystal deposits, and interstitial inflammation of the animals affected. Levels of oxaluria were also higher in the OX group [ 9 , 10 ].…”

Section: Methodsmentioning

confidence: 99%

“…Urolithiasis is an independent risk factor for the development of CKD [ 8 ], and obesity and metabolic syndrome contribute to the impairment of renal structure and function that leads to kidney failure when concurrent with lithiasic disorders. Experimental studies have further demonstrated the implication of OS in the exacerbation of the inflammatory response and kidney failure when concurrent with conditions such as obesity and hyperoxaluria [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

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

Medina

Muñoz

Rodríguez

et al. 2022

Cells

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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 objective of this paper was to characterize urolithiasis-related endothelial dysfunction in a hyperoxaluria rat model of renal lithiasis. Experimental approach: Characterization of endothelial dysfunction was assessed on 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 RNAm expression of proteins by RT-PCR and immunofluorescence. 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-κB, MCP-1 and TNFα 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-κB. 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’ impairment and normalized NADPH oxidase-dependent higher values of the 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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Metabolic syndrome contributes to renal injury mediated by hyperoxaluria in a murine model of nephrolithiasis

Cited by 9 publications

References 21 publications

Urolithiasis Develops Endothelial Dysfunction as a Clinical Feature

Urolithiasis Develops Endothelial Dysfunction as a Clinical Feature

A pilot dynamic analysis of formative factors of nephrolithiasis related to metabolic syndrome: evidence in a rat model

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

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