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Protective effect of berberine on high glucose and hypoxia-induced apoptosis via the modulation of HIF-1? in renal tubular epithelial cells.

ABSTRACT: Berberine (BBR), derived from Huanglian (Coptis chinensis), is a traditional Chinese herbal medicine. In the current study, we investigated the effects of BBR in high glucose (HG) and hypoxia-induced apoptosis with normal rat renal tubular epithelial (NRK-52E) and human kidney proximal tubular cells (HK-2) and further explored the underlying molecular mechanism of hypoxia-inducible factor 1? (HIF-1?) in diabetic kidney disease (DKD). Apoptosis in NRK-52E and HK-2 cells induced by HG (30 mM)/hypoxia and anti-apoptosis with BBR pretreatment (30 ?M) were analyzed by using the terminal uridine nick 3' end labeling method. Activities of apoptotic proteins and anti-apoptotic factor at mRNA and protein levels were determined with real-time RT-PCR and Western blot. HIF-1? action in the apoptosis with BBR pretreatment or siRNA interfere was investigated with flow-cytometry and Western blot. Up-regulation of apoptotic proteins (Bax cytochrome C, caspase 9 and caspase 3) and down-regulation of anti-apoptotic factor Bcl-xL were accompanied with HG/Hypoxia-induced apoptosis in NRK-52E and HK-2 cells but all reversals were found after BBR pretreatment. Activity of HIF-1? was induced under HG/Hypoxia conditions and up-regulated with BBR pretreatment. Furthermore, knockdown of HIF-1? via siRNA significantly removed the anti-apoptosis effects of BBR, while the BBR-mediated HIF-1? activity was suppressed by the pharmacological inhibition of Akt. The present study thereby provided evidence that BBR protected renal tubular epithelial cells from hypoxia/HG-induced apoptosis through activation of HIF-1? in the PI3K/Akt signal pathway and suggested that BBR could be a potential drug in DKD.

SUBMITTER: Zhang X

PROVIDER: S-EPMC6413295 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Protective effect of berberine on high glucose and hypoxia-induced apoptosis via the modulation of HIF-1α in renal tubular epithelial cells.

Zhang Xiuli X Guan Tingwen T Yang Boxuan B Chi Zhihong Z Wan Qijun Q Gu Harvest F HF

American journal of translational research 20190215 2

Berberine (BBR), derived from Huanglian (<i>Coptis chinensis</i>), is a traditional Chinese herbal medicine. In the current study, we investigated the effects of BBR in high glucose (HG) and hypoxia-induced apoptosis with normal rat renal tubular epithelial (NRK-52E) and human kidney proximal tubular cells (HK-2) and further explored the underlying molecular mechanism of hypoxia-inducible factor 1α (HIF-1α) in diabetic kidney disease (DKD). Apoptosis in NRK-52E and HK-2 cells induced by HG (30 m ...[more]

PMID: 30899370

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Project description:BackgroundThe morbidity of nephrolithiasis is 2-3 times higher in males than in females, suggesting that androgen plays a key role in nephrolithiasis. The death of renal tubular epithelial cells (TECs) is an important pathophysiological process contributing to the development of nephrolithiasis. Therefore, the aim of this study is to investigate whether androgen directly induces TECs apoptosis and necrosis and its underlying mechanisms in kidney stone formation.Materials and methodsWe compared serum testosterone level between male and female healthy volunteers and kidney stone patients. The in vivo nephrolithiasis model was established using glyoxylic acid, and calcium deposits were detected by van Kossa staining. In the in vitro study using mouse TECs (TCMK-1 cells) and human TECs (HK-2 cells), apoptosis, necrosis, and the expression of BH3-only protein Bcl-2-like 19 kDa-interacting protein 3 (BNIP3) were examined incubated with different doses of testosterone using flow cytometry. Levels of apoptosis-related proteins transfected with the BNIP3 siRNA were examined by western blotting. The mitochondrial potential (ΔΨm) was detected by JC-1 staining and flow cytometry. We monitored BNIP3 expression in the testosterone-induced TECs injury model after treatment with hypoxia inducible factor 1α (HIF-1α) and/or hypoxia inducible factor 2α (HIF-2α) inhibitors to determine the upstream protein regulating BNIP3 expression. Additionally, ChIP and luciferase assays were performed to confirm the interaction between HIF-1α and BNIP3.ResultsBoth male and female patients have significantly higher testosterones compared with healthy volunteers. More calcium deposits in the medulla were detected in male mice compared to female and castrated male mice. Testosterone induced TECs apoptosis and necrosis and increased BNIP3 expression in a dose-dependent manner. Testosterone also increased Bax expression, decreased Bcl-2 expression and induced a loss of ΔΨm. This effect was reversed by BNIP3 knockdown. HIF-1α inhibition significantly decreased BNIP3 expression and protected TECs from testosterone-induced apoptosis and necrosis. HIF-2α inhibition, however, did not influence BNIP3 expression or TECs apoptosis or necrosis. Finally, HIF-1α interacted with the BNIP3 promoter region.ConclusionBased on these results, testosterone induced renal TECs death by activating the HIF-1α/BNIP3 pathway.

Dataset Information

Protective effect of berberine on high glucose and hypoxia-induced apoptosis via the modulation of HIF-1? in renal tubular epithelial cells.

Publications

Protective effect of berberine on high glucose and hypoxia-induced apoptosis via the modulation of HIF-1α in renal tubular epithelial cells.

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