Gentamicin-Induced Acute Kidney Injury in an Animal Model Involves Programmed Necrosis of the Collecting Duct
Autor: | Heyu Ji, Hua A. Jenny Lu, William Jin, Huihui Huang, Ming Huang, Junying Yuan, Teodor G. Păunescu, Diane E. Capen, Yin Xia |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Programmed cell death Necrosis Indoles Necroptosis 030232 urology & nephrology Pharmacology 03 medical and health sciences RIPK1 Mice 0302 clinical medicine medicine Animals Kidney Tubules Collecting Protein kinase A Cells Cultured business.industry Aminoglycoside Acute kidney injury Imidazoles General Medicine Acute Kidney Injury medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology Basic Research Nephrology Apoptosis Receptor-Interacting Protein Serine-Threonine Kinases medicine.symptom Gentamicins business Protein Kinases |
Zdroj: | J Am Soc Nephrol |
ISSN: | 1533-3450 |
Popis: | BACKGROUND: Gentamicin is a potent aminoglycoside antibiotic that targets gram-negative bacteria, but nephrotoxicity limits its clinical application. The cause of gentamicin-induced AKI has been attributed mainly to apoptosis of the proximal tubule cells. However, blocking apoptosis only partially attenuates gentamicin-induced AKI in animals. METHODS: Mice treated with gentamicin for 7 days developed AKI, and programmed cell death pathways were examined using pharmacologic inhibitors and in RIPK3-deficient mice. Effects in porcine and murine kidney cell lines were also examined. RESULTS: Gentamicin caused a low level of apoptosis in the proximal tubules and significant ultrastructural alterations consistent with necroptosis, occurring predominantly in the collecting ducts (CDs), including cell and organelle swelling and rupture of the cell membrane. Upregulation of the key necroptotic signaling molecules, mixed lineage kinase domain-like pseudokinase (MLKL) and receptor-interacting serine/threonine-protein kinase 3 (RIPK3), was detected in gentamicin-treated mice and in cultured renal tubule cells. In addition, gentamicin induced apical accumulation of total and phosphorylated MLKL (pMLKL) in CDs in mouse kidney. Inhibiting a necroptotic protein, RIPK1, with necrostatin-1 (Nec-1), attenuated gentamicin-induced necrosis and upregulation of MLKL and RIPK3 in mice and cultured cells. Nec-1 also alleviated kidney inflammation and fibrosis, and significantly improved gentamicin-induced renal dysfunction in mice. Furthermore, deletion of RIPK3 in the Ripk3(−/−) mice significantly attenuated gentamicin-induced AKI. CONCLUSIONS: A previously unrecognized role of programmed necrosis in collecting ducts in gentamicin-induced kidney injury presents a potential new therapeutic strategy to alleviate gentamicin-induced AKI through inhibiting necroptosis. |
Databáze: | OpenAIRE |
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