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N-acetylcysteine with apocynin prevents hyperoxaluria-induced mitochondrial protein perturbations in nephrolithiasis
Minu Sharma1, Amit Sud2, Tanzeer Kaur3
1a Department of Biochemistry , Panjab University , Chandigarh , India ;
Abstract:
Diminished mitochondrial activities were deemed to play an imperative role in surged oxidative damage perceived in hyperoxaluric renal tissue. Proteomics is particularly valuable to delineate the damaging effects of oxidative stress on mitochondrial proteins. The present study was designed to apply large-scale proteomics to describe systematically how mitochondrial proteins/pathways govern the renal damage and calcium oxalate crystal adhesion in hyperoxaluria. Furthermore, the potential beneficial effects of combinatorial therapy with N-acetylcysteine (NAC) and apocynin were studied to establish its credibility in the modulation of hyperoxaluria-induced alterations in mitochondrial proteins. In an experimental setup with male Wistar rats, five groups were designed for 9 d. At the end of the experiment, 24-h urine was collected and rats were euthanized. Urinary samples were analyzed for kidney injury marker and creatinine clearance. Transmission electron microscopy revealed distorted renal mitochondria in hyperoxaluria but combinatorial therapy restored the normal mitochondrial architecture. Mitochondria were isolated from renal tissue of experimental rats, and mitochondrial membrane potential was analyzed. The two-dimensional electrophoresis (2-DE) based comparative proteomic analysis was performed on proteins isolated from renal mitochondria. The results revealed eight differentially expressed mitochondrial proteins in hyperoxaluric rats, which were identified by Matrix-assisted laser desorption/ionization time of flight/time of flight (MALDI-TOF/TOF) analysis. Identified proteins including those involved in important mitochondrial processes, e.g. antioxidant defense, energy metabolism, and electron transport chain. Therapeutic administration of NAC with apocynin significantly expunged hyperoxaluria-induced discrepancy in the renal mitochondrial proteins, bringing them closer to the controls. The results provide insights to further understand the underlying mechanisms in the development of hyperoxaluria-induced nephrolithiasis and the therapeutic relevance of the combinatorial therapy.
Insights
Hyperoxaluric kidney damage involves mitochondrial dysfunction and oxidative stress. Combined N-acetylcysteine (NAC) and apocynin therapy restored mitochondrial function and protein levels, offering therapeutic potential for kidney stones.
Area of Science:
- Biochemistry
- Nephrology
- Mitochondrial Biology
Background:
- Mitochondrial dysfunction and oxidative stress are implicated in hyperoxaluric kidney damage.
- Proteomics offers a valuable approach to identify proteins affected by oxidative stress in mitochondria.
- Understanding these changes is crucial for developing effective treatments for hyperoxaluric nephrolithiasis.
Purpose of the Study:
- To systematically investigate mitochondrial protein alterations in hyperoxaluric renal tissue using large-scale proteomics.
- To elucidate the role of mitochondrial proteins and pathways in renal damage and calcium oxalate crystal adhesion.
- To evaluate the therapeutic efficacy of combined N-acetylcysteine (NAC) and apocynin in modulating these hyperoxaluric alterations.
Main Methods:
- Male Wistar rats were divided into five groups for a 9-day experimental period.
- Proteomic analysis using two-dimensional electrophoresis (2-DE) was performed on isolated renal mitochondria.
- Differentially expressed proteins were identified using Matrix-assisted laser desorption/ionization time of flight/time of flight (MALDI-TOF/TOF) mass spectrometry.
Main Results:
- Hyperoxaluric rats exhibited distorted renal mitochondria, which were normalized by combinatorial therapy.
- Eight differentially expressed mitochondrial proteins involved in antioxidant defense, energy metabolism, and electron transport chain were identified.
- Combined NAC and apocynin treatment significantly reversed hyperoxaluric-induced changes in mitochondrial proteins.
Conclusions:
- Hyperoxaluria induces significant alterations in mitochondrial proteins, contributing to renal damage and crystal adhesion.
- Combined therapy with NAC and apocynin demonstrates significant therapeutic potential in ameliorating hyperoxaluric nephropathy.
- This study provides insights into the mechanisms of hyperoxaluric nephrolithiasis and the benefits of this combinatorial treatment.
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