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Updated: Aug 21, 2026
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Link between free radicals and protein kinase C in glucose-induced alteration of vascular dilation
Momoh A Yakubu1, Olusoga A Sofola, Immaculata Igbo
1Vascular Biology Unit, Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, 3100 Cleburne Avenue, Suite 2018 Gray Hall, Houston, TX 77004, USA. yakubu_ma@tsu.edu
Abstract:
Development of vascular complications in diabetes has been linked to the quality of glucose regulation and characterized by endothelial dysfunction. The exact mechanism behind vascular complications in diabetes is poorly understood. However, alteration of nitric oxide (NO) biosynthesis or bioactivity is strongly implicated and the mechanism behind such alterations is still a subject for research investigations. In the present study, we tested the hypothesis that glucose-induced attenuation of vascular relaxation involves protein kinase C (PKC)-linked generation of free radicals. Vascular relaxation to acetylcholine (ACh; 10(-9)-10(-5) M), isoproterenol (10(-9)-10(-5) M), or NO donor, sodium nitropruside (SNP; 10(-9)-10(-6) M) was determined in phenylephrine (PE, 10(-7) M) pre-constricted aortic rings from Sprague-Dawley rats in the presence or absence of 30 mM glucose (30 min), L-nitro-arginine methyl ester (L-NAME; 10(-4) M for 15 min), a NO synthase inhibitor, or xanthine (10(-5) M), a free radical generator. ACh dose-dependently caused relaxation that was attenuated by L-NAME, glucose, or xanthine. Pre-incubation (15 min) of the rings with vitamin C (10(-4) M), an antioxidant or calphostin C (10(-6) M), a PKC inhibitor, restored the ACh responses. However, high glucose had no significant effects on SNP or isoproterenol-induced relaxation. ACh-induced NO production by aortic ring was significantly reduced by glucose or xanthine. The reduced NO production was restored by pretreatment with vitamin C or calphostin C in the presence of glucose, but not xanthine. These data demonstrate that oxidants or PKC contribute to glucose-induced attenuation of vasorelaxation which could be mediated via impaired endothelial NO production and bioavailability. Thus, pathogenesis of glucose-induced vasculopathy involves PKC-coupled generation of oxygen free radicals which inhibit NO production and selectively inhibit NO-dependent relaxation.
Insights
High glucose impairs blood vessel relaxation by reducing nitric oxide (NO) production, involving protein kinase C (PKC) and free radicals. Antioxidants and PKC inhibitors restore NO function, suggesting a mechanism for diabetic vasculopathy.
Area of Science:
- Cardiovascular Biology
- Endocrinology
- Molecular Medicine
Background:
- Diabetic vascular complications are linked to poor glucose control and endothelial dysfunction.
- The precise mechanisms underlying diabetic vascular complications remain unclear.
- Alterations in nitric oxide (NO) biosynthesis and bioactivity are implicated, but underlying mechanisms require investigation.
Purpose of the Study:
- To test the hypothesis that glucose-induced attenuation of vascular relaxation involves protein kinase C (PKC)-linked free radical generation.
- To investigate the role of PKC and oxidants in glucose-mediated endothelial dysfunction.
Main Methods:
- Vascular relaxation responses to acetylcholine (ACh), isoproterenol, and sodium nitroprusside (SNP) were measured in rat aortic rings.
- Rings were exposed to high glucose, nitric oxide synthase inhibitor (L-NAME), or a free radical generator (xanthine).
- Effects of antioxidants (vitamin C) and a PKC inhibitor (calphostin C) on relaxation and NO production were assessed.
Main Results:
- High glucose and xanthine attenuated acetylcholine-induced relaxation and NO production.
- L-NAME also inhibited acetylcholine-induced relaxation, confirming NO dependency.
- Vitamin C and calphostin C restored ACh responses and NO production in glucose-treated rings, but not in xanthine-treated rings.
Conclusions:
- Glucose-induced attenuation of vasorelaxation involves PKC-coupled generation of oxygen free radicals.
- These radicals impair endothelial nitric oxide (NO) production and bioavailability, contributing to diabetic vasculopathy.
- PKC activation and oxidative stress are key mediators in the pathogenesis of glucose-induced vascular dysfunction.
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