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The Novel Compound Sul-121 Preserves Endothelial Function and Inhibits Progression of Kidney Damage in Type 2
S P H Lambooy1, A Bidadkosh1, D Nakladal1,2
1Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Abstract:
Diabetic nephropathy is still a common complication of type 2 diabetes mellitus (T2DM) and improvement of endothelial dysfunction (ED) and inhibition of reactive oxygen species (ROS) are considered important targets for new therapies. Recently, we developed a new class of compounds (Sul compounds) which inhibit mitochondrial ROS production. Here, we tested the therapeutic effects of Sul-121 on ED and kidney damage in experimental T2DM. Diabetic db/db and lean mice were implanted with osmotic pumps delivering Sul-121 (2.2 mg/kg/day) or vehicle from age 10 to 18 weeks. Albuminuria, blood pressure, endothelial mediated relaxation, renal histology, plasma creatinine, and H2O2 levels were assessed. Sul-121 prevented progression of albuminuria and attenuated kidney damage in db/db, as evidenced by lower glomerular fibronectin expression (~50%), decreased focal glomerular sclerosis score (~40%) and normalization of glomerular size and kidney weight. Further, Sul-121 restored endothelium mediated vasorelaxation through increased production of Nitric Oxide production and normalized plasma H2O2 levels. Sul-121 treatment in lean mice demonstrated no observable major side-effects, indicating that Sul-121 is well tolerated. Our data show that Sul-121 inhibits progression of diabetic kidney damage via a mechanism that involves restoration of endothelial function and attenuation of oxidative stress.
Insights
Sul-121, a novel compound, effectively treats diabetic nephropathy by improving endothelial function and reducing oxidative stress in type 2 diabetes mellitus. This therapeutic approach shows promise for inhibiting kidney damage progression.
Area of Science:
- Nephrology
- Endocrinology
- Pharmacology
Background:
- Diabetic nephropathy is a common complication of type 2 diabetes mellitus (T2DM).
- Endothelial dysfunction (ED) and reactive oxygen species (ROS) are key targets for T2DM therapies.
- Mitochondrial ROS production is a focus for new therapeutic compounds.
Purpose of the Study:
- To evaluate the therapeutic effects of Sul-121 on ED and kidney damage in experimental T2DM.
- To assess Sul-121's impact on oxidative stress and endothelial function in diabetic mice.
Main Methods:
- Diabetic (db/db) and lean mice received Sul-121 or vehicle via osmotic pumps from 10 to 18 weeks of age.
- Assessed outcomes included albuminuria, blood pressure, endothelial relaxation, renal histology, plasma creatinine, and H2O2 levels.
Main Results:
- Sul-121 prevented albuminuria progression and attenuated kidney damage in db/db mice.
- Observed benefits included reduced fibronectin, decreased glomerulosclerosis, normalized kidney weight, and glomerular size.
- Sul-121 restored endothelium-dependent vasorelaxation, increased nitric oxide production, and normalized plasma H2O2 levels.
- Sul-121 was well-tolerated in lean mice with no major side effects.
Conclusions:
- Sul-121 inhibits the progression of diabetic kidney damage.
- The mechanism involves restoring endothelial function and reducing oxidative stress.
