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

ABSTRACT: 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-? (TNF-?), 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.

SUBMITTER: Su L

PROVIDER: S-EPMC7475465 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Su Luyu L Cao Ping P Wang Haiyan H

Annals of translational medicine 20200801 16

<h4>Background</h4>Diabetic nephropathy (DN) is the leading cause of morbidity and mortality in diabetic patients. Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid isolated from the roots of <i>Stephania tetrandra</i>, 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.<h4>Methods</h4><i>In vitro</i> study, rats were divided into five groups (n=10): the control ...[more]

PMID: 32953790

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Project description:Diabetic nephropathy (DN) is a common complication in patients with diabetes and a leading cause of mortality. The management of DN in the clinic still remains a challenge. Therefore, the identification of novel compounds for DN treatment and their characterization in preclinical DN models are crucial. Isoeucommin A is a lignan compound isolated from Eucommia ulmoides Oliv, which has not been studied in detail. Our aim was to investigate the effect of Isoeucommin A in DN and to elucidate the molecular mechanisms though which Isoeucommin A acts in vitro and in vivo. We first isolated and purified Isoeucommin A by microporous resin column chromatography and studied the mass spectrogram, as well as the structure of Isoeucommin A, by high-resolution electrospray ionization mass spectroscopy and NMR, respectively. We further established an in vivo rat DN model and measured the changes of blood glucose, body weight, kidney index (KI), blood urea nitrogen, creatinine (CRE), glutathione, malondialdehyde (MDA), SOD, albumin (ALB) and urinary ALB to CRE ratios on treatment with Isoeucommin A. In addition, we measured SOD, MDA, glycogen synthase kinase-3β (GSK-3β), phosphorylated (p)-GSK-3β, nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels by quantitative real-time PCR and western blot, and estimated cell viability by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. After Isoeucommin A treatment, body weight, as well as SOD, glutathione, HO-1 and Nrf2 expression levels, in DN rats increased in a dose-dependent manner. In contrast, the levels of blood glucose, KI, blood urea nitrogen, CRE, urinary ALB to CRE ratio, tumor necrosis factor-α, interleukin-1β, interleukin-6 and MDA decreased significantly. In addition, Isoeucommin A protected H2 O2 -stimulated renal tubular epithelial cells from oxidative stress and activated the Nrf2/HO-1 signaling pathway in high-glucose-stimulated human renal mesangial cells. In conclusion, Isoeucommin A could alleviate inflammation and oxidative stress in in vitro and in vivo DN models and thus attenuate kidney injury by activating the Nrf2/HO-1 signaling pathway. Isoeucommin A could have the potential to be used as an effective drug for the treatment of DN.

Project description:Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. It is highly resistant to chemotherapy, and tumor recurrence is common. Neuronal precursor cell-expressed developmentally downregulated 4-1 (NEDD4-1) is an E3 ligase that controls embryonic development and animal growth. NEDD4-1 regulates the tumor suppressor phosphatase and tensin homolog (PTEN), one of the major regulators of the PI3K/AKT/mTOR signaling axis, as well as the response to oxidative stress. The expression levels of NEDD4-1 in GBM tissues and different cell lines were determined by quantitative real-time polymerase chain reaction and immunohistochemistry. In vitro and in vivo assays were performed to explore the biological effects of NEDD4-1 on GBM cells. Temozolomide (TMZ)-resistant U87MG and U251 cell lines were specifically established to determine NEDD4-1 upregulation and its effects on the tumorigenicity of GBM cells. Subsequently, miRNA expression in TMZ-resistant cell lines was investigated to determine the dysregulated miRNA underlying the overexpression of NEDD4-1. Indole-3-carbinol (I3C) was used to inhibit NEDD4-1 activity, and its effect on chemoresistance to TMZ was verified. NEDD4-1 was significantly overexpressed in the GBM and TMZ-resistant cells and clinical samples. NEDD4-1 was demonstrated to be a key oncoprotein associated with TMZ resistance, inducing oncogenicity and tumorigenesis of TMZ-resistant GBM cells compared with TMZ-responsive cells. Mechanistically, TMZ-resistant cells exhibited dysregulated expression of miR-3129-5p and miR-199b-3p, resulting in the induced NEDD4-1 mRNA-expression level. The upregulation of NEDD4-1 attenuated PTEN expression and promoted the AKT/NRF2/HO-1 oxidative stress signaling axis, which in turn conferred amplified defense against reactive oxygen species (ROS) and eventually higher resistance against TMZ treatment. The combination treatment of I3C, a known inhibitor of NEDD4-1, with TMZ resulted in a synergistic effect and re-sensitized TMZ-resistant tumor cells both in vitro and in vivo. These findings demonstrate the critical role of NEDD4-1 in regulating the redox imbalance in TMZ-resistant GBM cells via the degradation of PTEN and the upregulation of the AKT/NRF2/HO-1 signaling pathway. Targeting this regulatory axis may help eliminate TMZ-resistant glioblastoma.

Dataset Information

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

Publications

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

Similar Datasets

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