Tetrandrine mediates renal function and redox homeostasis in a streptozotocin-induced diabetic nephropathy rat model through Nrf2/HO-1 reactivation

Background: Diabetic nephropathy (DN) is the leading cause of morbidity and mortality in diabetic patients. Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid isolated from the roots of Stephania tetrandra, possesses anti-oxidative, anti-hypertensive, anti-inflammatory capacities. In this study, the maintenance role of Tet in DN was evaluated in streptozotocin (STZ)-induced diabetic rats.

Methods: In vitro study, rats were divided into five groups (n=10): the control group, the DN model group, the Tet-treatment group (5, 15, 30 mg/kg). DN damage was assessed by levels of blood glucose, serum creatinine (CRE), proteinuria, and urea nitrogen. ELISA assay was used to detecte tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6) and IL-10 levels. Kits were used to detecte contents of malondialdehyde (MDA), lactate dehydrogenase (LDH) and superoxide dismutase (SOD). Dichlorofluorescein (DCF) staining was used to detecte reactive oxygen species (ROS). HE staining assessed pathological damage. TUNEL staining assessed tissue apoptosis. Western Blot (WB) was used to detecte levels of Ki67, Survivin, Bax, Bcl-2, caspase-3, -9, c-Myc, nuclear factor erythroid-derived 2-related factor 2 (Nrf2), p-Nrf2, and heme oxygenase-1 (HO-1).

Results: Compared with the control group, STZ-induced significantly inhibited proliferation proteins' level, activated oxidative stress, aggravated tissue inflammation and promoted tissue apoptosis. STZ-induced further aggravated DN damage. Of note, these anomalies were restored by Tet pretreatment. Additionally, Tet upgraded the expression of p-Nrf2 and HO-1.

Conclusions: These results indicated that Tet could significantly restrain diabetic process and renal damage. Tet is a potential therapeutic agent in DN treatment via the reactivation of the Nrf2/HO-1.

Keywords: Diabetic nephropathy (DN); nuclear factor erythroid-derived 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1); oxidative stress; renal function; tetrandrine (Tet).