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Published on: June 16, 2014
Effects of Tolvaptan on Oxidative Stress in ADPKD: A Molecular Biological Approach
Matteo Rigato1, Gianni Carraro1, Irene Cirella1
1Department of Medicine, Nephrology, Dialysis and Transplantation Unit, University of Padova, 35128 Padova, Italy.
Abstract:
Autosomal dominant polycystic disease (ADPKD) is the most frequent monogenic kidney disease. It causes progressive renal failure, endothelial dysfunction, and hypertension, all of which are strictly linked to oxidative stress (OxSt). Treatment with tolvaptan is known to slow the renal deterioration rate, but not all the molecular mechanisms involved in this effect are well-established. We evaluated the OxSt state in untreated ADPKD patients compared to that in tolvaptan-treated ADPKD patients and healthy subjects. OxSt was assessed in nine patients for each group in terms of mononuclear cell p22phox protein expression, NADPH oxidase key subunit, MYPT-1 phosphorylation state, marker of Rho kinase activity (Western blot) and heme oxygenase (HO)-1, induced and protective against OxSt (ELISA). p22phox protein expression was higher in untreated ADPKD patients compared to treated patients and controls: 1.42 ± 0.11 vs. 0.86 ± 0.15 d.u., p = 0.015, vs. 0.53 ± 0.11 d.u., p < 0.001, respectively. The same was observed for phosphorylated MYPT-1: 0.96 ± 0.28 vs. 0.68 ± 0.09 d.u., p = 0.013 and vs. 0.47 ± 0.13 d.u., p < 0.001, respectively, while the HO-1 expression of untreated patients was significantly lower compared to that of treated patients and controls: 5.33 ± 3.34 vs. 2.08 ± 0.79 ng/mL, p = 0.012, vs. 1.97 ± 1.22 ng/mL, p = 0.012, respectively. Tolvaptan-treated ADPKD patients have reduced OxSt levels compared to untreated patients. This effect may contribute to the slowing of renal function loss observed with tolvaptan treatment.
Insights
Autosomal dominant polycystic kidney disease (ADPKD) involves oxidative stress (OxSt). Tolvaptan treatment reduces OxSt markers in ADPKD patients, potentially slowing kidney function decline.
Area of Science:
- Nephrology
- Molecular Biology
- Oxidative Stress Research
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of inherited kidney failure.
- Oxidative stress (OxSt) is implicated in ADPKD pathogenesis, contributing to renal dysfunction, hypertension, and endothelial issues.
- Tolvaptan is a treatment that slows ADPKD progression, but its precise molecular mechanisms, particularly regarding OxSt, require further elucidation.
Purpose of the Study:
- To compare the oxidative stress (OxSt) status between untreated ADPKD patients, tolvaptan-treated ADPKD patients, and healthy controls.
- To investigate the impact of tolvaptan treatment on specific molecular markers of OxSt in ADPKD.
Main Methods:
- Evaluated OxSt in nine patients per group (untreated ADPKD, tolvaptan-treated ADPKD, healthy controls).
- Assessed mononuclear cell p22phox protein expression (NADPH oxidase subunit) using Western blot.
- Measured MYPT-1 phosphorylation (Rho kinase activity marker) via Western blot.
- Quantified heme oxygenase (HO)-1 expression (an OxSt-protective enzyme) using ELISA.
Main Results:
- Untreated ADPKD patients exhibited significantly higher p22phox expression compared to both treated patients and controls.
- Phosphorylated MYPT-1 levels were elevated in untreated ADPKD patients relative to treated patients and controls.
- HO-1 expression was significantly lower in untreated ADPKD patients compared to tolvaptan-treated patients and healthy subjects.
Conclusions:
- Tolvaptan treatment is associated with reduced oxidative stress markers in ADPKD patients.
- The observed decrease in OxSt may be a key mechanism by which tolvaptan slows the progression of renal function loss in ADPKD.
- These findings highlight the role of oxidative stress in ADPKD and the potential benefits of targeting it with tolvaptan.
