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MnTBAP Therapy Attenuates Renal Fibrosis in Mice with 5/6 Nephrectomy
Jing Yu1, Song Mao1, Yue Zhang1
1Department of Nephrology, Nanjing Children's Hospital, Nanjing Medical University, Nanjing 210008, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China; Nanjing Key Laboratory of Pediatrics, Nanjing 210008, China.
Abstract:
Renal fibrosis is a common pathological feature of all kinds of chronic kidney diseases (CKDs) with uncertain mechanisms. Accumulating evidence demonstrated an important role of oxidative stress in the pathogenesis of CKD. Here we hypothesized that MnTBAP (manganese (III) tetrakis (4-benzoic acid)porphyrin chloride), a cell-permeable mimic of superoxide dismutase (SOD), may protect against the fibrotic response in CKD by antagonizing oxidative stress. To verify this hypothesis, we performed experiments in tubular epithelial cells and mice with 5/6 nephrectomy (Nx). In mouse tubular epithelial cells, TGF-β1 induced a significant transition to fibrotic phenotype in line with a remarkable mitochondrial dysfunction, which was markedly improved by MnTBAP (1.14 μM) pretreatment. In remnant kidneys of 5/6 Nx mice, tubulointerstitial fibrosis occurred in parallel with mitochondrial abnormality in renal tubular cells. Administration of MnTBAP significantly attenuated the deposition of extracellular matrix as evidenced by the blocked expressions of fibronectin, collagen I, and collagen III. Masson staining also displayed an ameliorated accumulation of collagenous matrix in MnTBAP-treated mice. Moreover, MnTBAP also significantly improved the severity of proteinuria without altering CKD-related hypertension. Collectively, MnTBAP therapy served as a promising strategy in preventing renal fibrosis in CKDs possibly via antagonizing mitochondrial-derived oxidative stress and subsequent protection of mitochondrial function.
Insights
Manganese (III) tetrakis (4-benzoic acid)porphyrin chloride) (MnTBAP) reduces kidney fibrosis in chronic kidney diseases (CKDs) by combating oxidative stress. This compound protects mitochondrial function and lessens extracellular matrix deposition in damaged kidneys.
Area of Science:
- Nephrology
- Pathology
- Biochemistry
Background:
- Renal fibrosis is a hallmark of chronic kidney diseases (CKDs), with its mechanisms not fully understood.
- Oxidative stress is increasingly recognized as a key factor in the development and progression of CKD.
- Manganese (III) tetrakis (4-benzoic acid)porphyrin chloride) (MnTBAP), a superoxide dismutase mimic, is investigated for its potential antifibrotic effects.
Purpose of the Study:
- To investigate the hypothesis that MnTBAP can protect against renal fibrosis in CKD by mitigating oxidative stress.
- To evaluate the efficacy of MnTBAP in preventing fibrotic responses in both cellular and animal models of kidney injury.
Main Methods:
- Experiments were conducted using mouse tubular epithelial cells and mice subjected to 5/6 nephrectomy (Nx).
- Tubular epithelial cells were treated with transforming growth factor-beta 1 (TGF-β1) to induce fibrosis and mitochondrial dysfunction, with MnTBAP used as a pretreatment.
- In 5/6 Nx mice, MnTBAP was administered to assess its impact on tubulointerstitial fibrosis, extracellular matrix deposition, and proteinuria.
Main Results:
- MnTBAP pretreatment significantly improved TGF-β1-induced fibrotic phenotype and mitochondrial dysfunction in tubular epithelial cells.
- In 5/6 Nx mice, MnTBAP administration attenuated tubulointerstitial fibrosis, reduced extracellular matrix deposition (fibronectin, collagen I, collagen III), and ameliorated proteinuria.
- MnTBAP treatment did not alter the established hypertension associated with CKD in the experimental model.
Conclusions:
- MnTBAP demonstrates a promising therapeutic potential for preventing renal fibrosis in chronic kidney diseases.
- The antifibrotic effects of MnTBAP are likely mediated through the antagonism of mitochondrial-derived oxidative stress and subsequent preservation of mitochondrial function.
- MnTBAP represents a potential strategy to protect kidney function in the context of fibrotic kidney diseases.
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