The present study evaluated the participation of oxidative stress in the pathophysiology of CI-AKI with DM as a risk factor and investigated the role of COQ-10 as a possible treatment for this pathology. Oxidative stress and inflammation status are correlated in the prognosis of CI-AKI in DM, therefore, the investigation of antioxidants alternatives that promote renoprotection is of great importance.
The development of CI-AKI in DM was evidenced in this study with dysfunctions in renal function, renal hemodynamics and the installation of oxidative damage. Clinically CI-AKI is defined an increase in serum creatinine ≥ 0.5 mg/dL or 25% increase of serum creatinine from the baseline value at 48 h after of contrast media administration .
The COQ-10 has demonstrated high therapeutic potential due to its antioxidant and anti-inflammatory activities in many injury models, including studies of nephrotoxicity by cisplatin and cyclosporine [15, 28, 29, 30]. Our results highlighted the role of COQ-10 in the modulation of pathophysiological processes induced by nephrotoxicity of IC, showing that the treatment with COQ-10 exerted a protective effect on the renal function of diabetic animals submitted to CI-AKI. The renoprotective effect was evidenced by the increase in inulin clearance and decrease in serum creatinine in DM animals that received IC and treatment with COQ-10.
Increased RVR and the decrease in RBF in DM after IC, as observed in this study, can be attributed to vasoconstriction due viscosity and osmolarity of contrast media. The vasoconstriction contributes to hypoxia and development of oxidative injury that culminate in endothelial dysfunction [4, 25]. Additionally, DM is associated with development of hypoxia inducible factors (HIF) that enhanced activity of renin-angiotensin system may also intensify the vasoconstriction via endothelin synthesis and increased effect of adenosine [2, 3]. In this study, treatment with COQ-10 demonstrated improvement in renal hemodynamics with reduced RVR and elevated RBF. Studies suggest that COQ-10 stimulates the production of prostaglandin-1 and prostacyclin, which aid in vasodilation, and reduce peripheral resistance by preserving the vasodilator nitric oxide, promoting the reduction of nitrogen dioxide to nitric oxide, helping to maintain this bioregulatory agent [11, 12].
In the present study, it was observed a significant increase of oxidative stress via TBARS, FOX and nitrate elevation and a reduction of thiols levels. Hyperglycemia increases oxidative stress in CI-AKI by activating stress-activated proteins kinase, functional proteins glycosylation, glucose autoxidation and the formation of reactive nitrogen species, such peroxynitrite, that has been related in the enhanced inflammation in diabetes by decreased nitric oxide bioavailability [10, 17, 31]. ROS production in DM has been linked to vasoconstriction, vascular cell hypertrophy and migration, endothelial dysfunction, modification of extracellular matrix proteins, and increased renal sodium reabsorption [3, 31]. Enhanced macrophage migration induces the release of inflammatory and profibrotic cytokines, stimulating greater ROS production. Thus, the oxidative stress induced by cytokine production in DM associated of contrast injury increase ROS establishing a vicious cycle [2, 32, 33, 34].
Despite its primary role in the production of ATP, COQ-10 is considered a substance of great antioxidant and anti-inflammatory activity, due capable of stabilize two free radicals to each molecule of COQ-10 in its redox cycle, is quickly recovered, may inhibit NF-kB and protein kinases, reduce free radical delivering them to recovery of antioxidants cycle, such vitamin E, efficiency in interrupting radical chain reactions such as lipid peroxidation, also to avoid nitrosative stress reacting [35, 36].
In this study, the treatment of diabetic animals with COQ-10 demonstrated the ability to preserve the reserve of systemic thiol anti-oxidant after IC administration. Intracellular antioxidants mechanisms such glutathione, a non-protein thiol, exercise role in neutralization of ROS, protecting against oxidative damage while their decrease contributes to the oxidative attack on cells. COQ-10 demonstrated to preserve glutiona in an animal model of cisplatin-induced nephrotoxicity by increase of selenium, necessary for the composition of glutathione [29, 37, 38].
In the present study, diabetic animals demonstrated mild tubulointerstitial changes typical of the development of diabetic nephropathy . The histological changes observed in animals that received IC were due to the association of the insult caused by hyperglycemia and IC, reinforcing that the mechanism involved in the reduction of renal function is mainly related to renal hemodynamic changes and oxidative damage that favor the installation of IC -AKI. Our findings indicate that the administration of COQ-10 prevented the progression of the extension area with tissue damage after the use of IC.
Considering that DM is a modifiable risk factor for IC nephrotoxicity, the implementation of preventive strategies with innovative pharmacological interventions, such as COQ-10, can establish a promising scenario and efficiently reverse the adverse effects of pathophysiology of the NIC.