Abstract

Adipokine leptin reportedly acts on the kidney in pathophysiological states. However, the influence of leptin on renal tubular epithelial cells is still unclear. Gentamicin, a widely used antibiotic for the treatment of bacterial infection, can cause nephrotoxicity. This study aims to investigate the influence of long-term leptin treatment on gentamicin-induced apoptosis in rat renal tubular cells (NRK-52E) and mice. We monitored apoptosis and molecular mechanisms using annexin V/ propidium iodide staining and small interfering RNA transfection. In NRK-52E cells, leptin reduced gentamicin-induced apoptosis at 24 h, but significantly increased apoptosis at 48 h. Long-term treatment of leptin decreased Bcl-xL expression and increased caspase activity in gentamicin-treated NRK-52E cells. Leptin also increased the expression of cyclooxygenase-2 (COX-2) and its product, prostaglandin E2 (PGE 2), in a dose-dependent manner. The COX-2 inhibitor, NS398 (N-[2-(Cyclohexyloxy)-4- nitrophenyl]methanesulfonamide), blocked PGE 2 augmentation and the pro-apoptotic effects of leptin. The addition of PGE2 recovered the pro-apoptotic effect of leptin in NS398-treated NRK-52E cells. In a mouse animal model, a 10 day leptin treatment significantly increased gentamicin-induced apoptotic cells in proximal tubules. NS398 treatment inhibited this in vivo pro-apoptotic effect of leptin. Results reveal that long-term elevation of leptin induces COX-2-mediated PGE2 augmentation in renal tubular cells, and then increases these cells' susceptibility to gentamicin-induced apoptosis.

Original languageEnglish
Pages (from-to)65-71
Number of pages7
JournalEuropean Journal of Pharmacology
Volume689
Issue number1-3
DOIs
Publication statusPublished - Aug 15 2012

Fingerprint

Leptin
Dinoprostone
Kidney
Gentamicins
Apoptosis
Cyclooxygenase 2
Adipokines
Propidium
Cyclooxygenase 2 Inhibitors
Annexin A5
Caspases
Bacterial Infections
Small Interfering RNA
Transfection
Animal Models
Epithelial Cells
Staining and Labeling
Anti-Bacterial Agents
N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide

Keywords

  • Apoptosis
  • Gentamicin
  • Leptin
  • Prostaglandin E2 (PGE )
  • Renal tubular cells

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Long-term leptin treatment exerts a pro-apoptotic effect on renal tubular cells via prostaglandin E2 augmentation",
abstract = "Adipokine leptin reportedly acts on the kidney in pathophysiological states. However, the influence of leptin on renal tubular epithelial cells is still unclear. Gentamicin, a widely used antibiotic for the treatment of bacterial infection, can cause nephrotoxicity. This study aims to investigate the influence of long-term leptin treatment on gentamicin-induced apoptosis in rat renal tubular cells (NRK-52E) and mice. We monitored apoptosis and molecular mechanisms using annexin V/ propidium iodide staining and small interfering RNA transfection. In NRK-52E cells, leptin reduced gentamicin-induced apoptosis at 24 h, but significantly increased apoptosis at 48 h. Long-term treatment of leptin decreased Bcl-xL expression and increased caspase activity in gentamicin-treated NRK-52E cells. Leptin also increased the expression of cyclooxygenase-2 (COX-2) and its product, prostaglandin E2 (PGE 2), in a dose-dependent manner. The COX-2 inhibitor, NS398 (N-[2-(Cyclohexyloxy)-4- nitrophenyl]methanesulfonamide), blocked PGE 2 augmentation and the pro-apoptotic effects of leptin. The addition of PGE2 recovered the pro-apoptotic effect of leptin in NS398-treated NRK-52E cells. In a mouse animal model, a 10 day leptin treatment significantly increased gentamicin-induced apoptotic cells in proximal tubules. NS398 treatment inhibited this in vivo pro-apoptotic effect of leptin. Results reveal that long-term elevation of leptin induces COX-2-mediated PGE2 augmentation in renal tubular cells, and then increases these cells' susceptibility to gentamicin-induced apoptosis.",
keywords = "Apoptosis, Gentamicin, Leptin, Prostaglandin E2 (PGE ), Renal tubular cells",
author = "Hsu, {Yung Ho} and Cheng, {Chung Yi} and Chen, {Yen Cheng} and Chen, {Tso Hsiao} and Sue, {Yuh Mou} and Tsai, {Wei Lun} and Chen, {Cheng Hsien}",
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AU - Hsu, Yung Ho

AU - Cheng, Chung Yi

AU - Chen, Yen Cheng

AU - Chen, Tso Hsiao

AU - Sue, Yuh Mou

AU - Tsai, Wei Lun

AU - Chen, Cheng Hsien

PY - 2012/8/15

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N2 - Adipokine leptin reportedly acts on the kidney in pathophysiological states. However, the influence of leptin on renal tubular epithelial cells is still unclear. Gentamicin, a widely used antibiotic for the treatment of bacterial infection, can cause nephrotoxicity. This study aims to investigate the influence of long-term leptin treatment on gentamicin-induced apoptosis in rat renal tubular cells (NRK-52E) and mice. We monitored apoptosis and molecular mechanisms using annexin V/ propidium iodide staining and small interfering RNA transfection. In NRK-52E cells, leptin reduced gentamicin-induced apoptosis at 24 h, but significantly increased apoptosis at 48 h. Long-term treatment of leptin decreased Bcl-xL expression and increased caspase activity in gentamicin-treated NRK-52E cells. Leptin also increased the expression of cyclooxygenase-2 (COX-2) and its product, prostaglandin E2 (PGE 2), in a dose-dependent manner. The COX-2 inhibitor, NS398 (N-[2-(Cyclohexyloxy)-4- nitrophenyl]methanesulfonamide), blocked PGE 2 augmentation and the pro-apoptotic effects of leptin. The addition of PGE2 recovered the pro-apoptotic effect of leptin in NS398-treated NRK-52E cells. In a mouse animal model, a 10 day leptin treatment significantly increased gentamicin-induced apoptotic cells in proximal tubules. NS398 treatment inhibited this in vivo pro-apoptotic effect of leptin. Results reveal that long-term elevation of leptin induces COX-2-mediated PGE2 augmentation in renal tubular cells, and then increases these cells' susceptibility to gentamicin-induced apoptosis.

AB - Adipokine leptin reportedly acts on the kidney in pathophysiological states. However, the influence of leptin on renal tubular epithelial cells is still unclear. Gentamicin, a widely used antibiotic for the treatment of bacterial infection, can cause nephrotoxicity. This study aims to investigate the influence of long-term leptin treatment on gentamicin-induced apoptosis in rat renal tubular cells (NRK-52E) and mice. We monitored apoptosis and molecular mechanisms using annexin V/ propidium iodide staining and small interfering RNA transfection. In NRK-52E cells, leptin reduced gentamicin-induced apoptosis at 24 h, but significantly increased apoptosis at 48 h. Long-term treatment of leptin decreased Bcl-xL expression and increased caspase activity in gentamicin-treated NRK-52E cells. Leptin also increased the expression of cyclooxygenase-2 (COX-2) and its product, prostaglandin E2 (PGE 2), in a dose-dependent manner. The COX-2 inhibitor, NS398 (N-[2-(Cyclohexyloxy)-4- nitrophenyl]methanesulfonamide), blocked PGE 2 augmentation and the pro-apoptotic effects of leptin. The addition of PGE2 recovered the pro-apoptotic effect of leptin in NS398-treated NRK-52E cells. In a mouse animal model, a 10 day leptin treatment significantly increased gentamicin-induced apoptotic cells in proximal tubules. NS398 treatment inhibited this in vivo pro-apoptotic effect of leptin. Results reveal that long-term elevation of leptin induces COX-2-mediated PGE2 augmentation in renal tubular cells, and then increases these cells' susceptibility to gentamicin-induced apoptosis.

KW - Apoptosis

KW - Gentamicin

KW - Leptin

KW - Prostaglandin E2 (PGE )

KW - Renal tubular cells

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