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Glibenclamide improves kidney and heart structure and function in the adenine-diet model of chronic kidney disease
Vishal Diwan1, Glenda Gobe2, Lindsay Brown3
1School of Biomedical Science, The University of Queensland, Australia; Centre for Kidney Disease Research, School of Medicine, The University of Queensland, Australia.
Abstract:
The development of chronic kidney disease (CKD) and associated cardiovascular disease involves free radical damage and inflammation. Addition of adenine to the diet induces inflammation followed by CKD and cardiovascular disease. NOD-like receptor protein-3 (NLRP-3) is pro-inflammatory in the kidney; glibenclamide inhibits production of NLRP-3. Male Wistar rats were fed either control rat food or adenine (0.25%) in this food for 16 weeks. Glibenclamide (10 mg/kg/day) was administered to two groups with and without adenine for the final 8 weeks. Kidney function (blood urea nitrogen/BUN, plasma creatinine/PCr, plasma uric acid, proteinuria), kidney structure (fibrosis, inflammation), cardiovascular parameters (blood pressure, left ventricular stiffness, vascular responses and echocardiography) and protein expression of markers for oxidative stress (HO-1), and inflammation (TNF-α, NLRP-3) were assessed. In adenine-fed rats, glibenclamide decreased BUN (controls: 6±0.6; adenine: 56.6±5.4; adenine+glibenclamide: 19.4±2.7 mmol/L), PCr (controls: 42±2.8; adenine: 268±23; adenine+glibenclamide: 81±10 μmol/L), proteinuria (controls: 150±7.4; adenine: 303±19; adenine+glibenclamide: 220±13 μmol/L) (all p<0.05). Glibenclamide decreased infiltration of chronic inflammatory cells, fibrosis, tubular damage and expression of HO-1, TNF-α and NLRP-3 in the kidney. Glibenclamide did not alter plasma uric acid concentrations (controls: 38±1; adenine: 63±4; adenine+glibenclamide: 69±14 μmol/L). Cardiovascular changes included decreased systolic blood pressure and improved vascular responses although cardiac fibrosis, left ventricular stiffness and hypertrophy were not reduced. Glibenclamide improved kidney structure and function in CKD and decreased some cardiovascular parameters. Inflammatory markers and cell populations were attenuated by glibenclamide in kidneys.
Insights
Glibenclamide treatment improved kidney function and structure in rats with adenine-induced chronic kidney disease (CKD). The drug reduced inflammation and oxidative stress markers, offering potential therapeutic benefits for CKD and related cardiovascular issues.
Area of Science:
- Nephrology
- Cardiovascular Medicine
- Pharmacology
Background:
- Chronic kidney disease (CKD) and associated cardiovascular disease are linked to inflammation and free radical damage.
- Dietary adenine induces inflammation, leading to CKD and cardiovascular complications.
- NOD-like receptor protein-3 (NLRP-3) is a key inflammatory mediator in the kidney, and glibenclamide is known to inhibit its production.
Purpose of the Study:
- To investigate the effects of glibenclamide on adenine-induced CKD and associated cardiovascular changes in male Wistar rats.
- To assess glibenclamide's impact on kidney function, structure, cardiovascular parameters, and key inflammatory and oxidative stress markers.
Main Methods:
- Male Wistar rats were fed a control diet or a diet supplemented with 0.25% adenine for 16 weeks.
- Glibenclamide (10 mg/kg/day) was administered to rats with and without adenine during the final 8 weeks.
- Evaluated kidney function (BUN, plasma creatinine, uric acid, proteinuria), kidney structure (fibrosis, inflammation), cardiovascular parameters (blood pressure, vascular responses, cardiac structure), and protein expression (HO-1, TNF-α, NLRP-3).
Main Results:
- Glibenclamide significantly reduced blood urea nitrogen, plasma creatinine, and proteinuria in adenine-fed rats.
- The drug decreased inflammatory cell infiltration, fibrosis, tubular damage, and expression of HO-1, TNF-α, and NLRP-3 in the kidneys.
- Glibenclamide lowered systolic blood pressure and improved vascular responses, but did not significantly alter plasma uric acid or reduce cardiac fibrosis, left ventricular stiffness, or hypertrophy.
Conclusions:
- Glibenclamide demonstrates renoprotective effects, improving kidney structure and function in a rat model of CKD.
- The therapeutic benefits are associated with the attenuation of renal inflammatory and oxidative stress markers.
- While glibenclamide improved some cardiovascular parameters, its effects on cardiac remodeling require further investigation.
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