A Role for Tubular Necroptosis in Cisplatin-Induced AKI

J Am Soc Nephrol. 2015 Nov;26(11):2647-58. doi: 10.1681/ASN.2014080741. Epub 2015 Mar 18.


Cell death and inflammation in the proximal tubules are the hallmarks of cisplatin-induced AKI, but the mechanisms underlying these effects have not been fully elucidated. Here, we investigated whether necroptosis, a type of programmed necrosis, has a role in cisplatin-induced AKI. We found that inhibition of any of the core components of the necroptotic pathway-receptor-interacting protein 1 (RIP1), RIP3, or mixed lineage kinase domain-like protein (MLKL)-by gene knockout or a chemical inhibitor diminished cisplatin-induced proximal tubule damage in mice. Similar results were obtained in cultured proximal tubular cells. Furthermore, necroptosis of cultured cells could be induced by cisplatin or by a combination of cytokines (TNF-α, TNF-related weak inducer of apoptosis, and IFN-γ) that were upregulated in proximal tubules of cisplatin-treated mice. However, cisplatin induced an increase in RIP1 and RIP3 expression in cultured tubular cells in the absence of cytokine release. Correspondingly, overexpression of RIP1 or RIP3 enhanced cisplatin-induced necroptosis in vitro. Notably, inflammatory cytokine upregulation in cisplatin-treated mice was partially diminished in RIP3- or MLKL-deficient mice, suggesting a positive feedback loop involving these genes and inflammatory cytokines that promotes necroptosis progression. Thus, our data demonstrate that necroptosis is a major mechanism of proximal tubular cell death in cisplatin-induced nephrotoxic AKI.

Keywords: cisplatin nephrotoxicity; necroptosis; renal proximal tubule cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Animals
  • Antineoplastic Agents / adverse effects
  • Apoptosis / drug effects*
  • Cisplatin / adverse effects*
  • Cytokines / metabolism
  • GTPase-Activating Proteins / metabolism*
  • Inflammation / pathology
  • Kidney Tubules / drug effects
  • Kidney Tubules / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Necrosis / chemically induced
  • Protein Kinases / metabolism*
  • RNA, Small Interfering / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism


  • Antineoplastic Agents
  • Cytokines
  • GTPase-Activating Proteins
  • RNA, Small Interfering
  • Ralbp1 protein, mouse
  • Tumor Necrosis Factor-alpha
  • MLKL protein, mouse
  • Protein Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • Cisplatin