Diabetes aggravates renal ischemia and reperfusion injury in rats by exacerbating oxidative stress, inflammation, and apoptosis

Abstract

Diabetic patients are more susceptible to renal ischemia/reperfusion (I/R) injury (RI/RI) and have a poor prognosis, but the underlying mechanism remains unclear. The present study aimed to examine whether diabetes could worsen acute kidney injury induced by I/R in rats and clarify its mechanism. Control and streptozotocin-induced diabetic rats were subjected to 45 min renal pedicle occlusion followed by 24 h reperfusion. Tert-butylhydroquinone (TBHQ, 16.7 mg/kg) was administrated intraperitoneally 3 times at intervals of 8 h before ischemia. Serum and kidneys were harvested after reperfusion to evaluate renal function and histological injury. Enzyme-linked immunosorbent assays were used to test pro-inflammatory cytokines. Terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling assays were used to detect apoptotic cells, and western blotting was performed to determine the expression of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved caspase-3, as well as oxidative stress and inflammation-related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Toll-like receptor 4 (TLR4), and nuclear factor-κB (NF-κB). Compared with control animals, diabetic rats undergoing I/R exhibited more severe tubular damage and renal dysfunction. Diabetes exacerbated oxidative stress, the inflammatory response, and apoptosis after renal I/R by enhancing TLR4/NF-κB signaling and blocking the Nrf2/HO-1 pathway. RI/RI in diabetic rats was attenuated by pretreatment with TBHQ (a Nrf2 agonist), which exerted anti-inflammatory and anti-apoptotic properties by inhibiting NF-κB signaling. These findings indicate that hyperglycemia exacerbates RI/RI by intensifying oxidative stress, inflammation, and apoptosis. Antioxidant pretreatment may alleviate RI/RI in diabetic patients.

Resveratrol inhibits TNF-α-induced inflammation to protect against renal ischemia/reperfusion injury in diabetic rats

“…This was usually accompanied by the release of inflammatory cytokines, such as TNF-α, IL-1β and IL-6. Studies 4 , 24 showed that the inflammatory response induced by I/R injury was further exacerbated in diabetic rats, in which TNF-a and IL-1β levels in serum or renal tissues increased significantly. In this study, we have demonstrated that administration of resveratrol proved to be effective to inhibit the expression of the pro-inflammatory cytokines TNF-α and IL-1β elevated in the kidney of diabetic rats after I/R injury.…”

Protective Role of Nrf2 in Renal Disease

“…Hyperglycemia aggravates renal injury caused by I/R. Treatment with tert-butylhydroquinone (TBHQ) reduced I/R-related injury during diabetes via Nrf2 activation, reducing cell death and oxidative stress [ 132 ]. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist used in the treatment of diabetes, also activates Nrf2 leading to an increase in antioxidant and anti-inflammatory defenses.…”

Tert-butylhydroquinone mitigates Carbon Tetrachloride induced Hepatic Injury in mice

“…In vivo, treatment of tBHQ showed markedly cytoprotective effect in many tissues under pathological condition [17,18]. Administration of tBHQ could inhibit ROS generation and reduce renal injury in renal ischemia and reperfusion model [19]. Continuous tBHQ treatment markedly decreased and ameliorated proteinuria in type 1 diabetes mice [20].…”