Hepatic, Gastrointestinal, Pulmonary and Renal Pharmacology

Prostaglandin E1 attenuates high glucose-induced apoptosis in proximal renal tubular cells by inhibiting the JNK/Bim pathway

Authors: Yu-han Zhang1, Ya-qin Zhang1,2, Cong-cong Guo3,4, Li-kang Wang1,3, Yu-jiao Cui1,3, Jian-jun Dong5, Lin Liao1,6
1 Division of Endocrinology, Department of Internal Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Ji-nan 250014, China
2 Division of Endocrinology, Department of Internal Medicine, Wuhan Third Hospital, Wuhan 430060, China
3 First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Ji-nan 250355, China
4 Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Ji-nan 250011, China
5 Division of Endocrinology, Department of Internal Medicine, Qilu Hospital of Shandong University, Ji-nan 250012, China
6 Division of Endocrinology, Department of Internal Medicine, the First Affiliated Hospital of Shandong First Medical University, Ji-nan 250014, China
Correspondence to: Jian-jun Dong: cwc_ll@sdu.edu.cn, Lin Liao: liaolin@sdu.edu.cn,
DOI: 10.1038/s41401-019-0314-9
Received: 9 May 2019
Accepted: 30 September 2019
Advance online: 4 November 2019

Abstract

Proximal renal tubular damage is a critical process underlying diabetic kidney disease (DKD). Our previous study shows that prostaglandin E1 (PGE1) reduces the apoptosis of renal tubular cells in DKD rats. But its underlying mechanisms remain unclear. In this study we investigated the protective effects of PGE1 in DKD rats and high glucose (HG, 30 mM)-treated HK-2 proximal tubular cells. Four weeks after uninephrectomized streptozotocin-induced diabetic rats were established, the DKD rats were administered PGE1 (10 µg· kg−1·d−1, iv.) for 10 consecutive days. We showed that PGE1 administration did not change blood glucose levels, but alleviated diabetic kidney injury in the DKD rats, evidenced by markedly reduced proteinuria and renal tubular apoptosis. In the in vitro experiments, PGE1 (0.1–100 µM) significantly enhanced HG-reduced HK-2 cell viability. In HG-treated HK-2 cells, PGE1 (10 µM) significantly suppressed the c-Jun N-terminal kinase (JNK) and the mitochondrial apoptosis-related protein expressions such as Bim, Bax, caspase-3 and cleaved caspase-3; similar changes were also observed in the kidney of PGE1-treated DKD rats. By using two pharmacological tools-JNK activator anisomycin (AM) and JNK inhibitor SP600125, we revealed that PGE1 blocked HG-triggered activation of JNK/Bim pathway in HK-2 cells; JNK was an upstream regulator of Bim. In conclusion, our results demonstrate that the nephroprotective effects of PGE1 against apoptosis of proximal renal tubule in DKD rats via suppressing JNK-related Bim signaling
Keywords: Diabetic kidney disease; proximal renal tubular cells; prostaglandin E1; apoptosis; JNK/Bim; HK-2 proximal tubular cells; anisomycin; SP600125

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