Rheb1 protects against cisplatin-induced tubular cell death and acute kidney injury via maintaining mitochondrial homeostasis

Cell Death Dis. 2020 May 13;11(5):364. doi: 10.1038/s41419-020-2539-4.


Ras homolog enriched in brain (Rheb1), a small GTPase, plays a crucial role in regulating cell growth, differentiation, and survival. However, the role and mechanisms for Rheb1 in tubular cell survival and acute kidney injury (AKI) remain unexplored. Here we found that Rheb1 signaling was activated in kidney tubule of AKI patients and cisplatin-treated mice. A mouse model of tubule-specific deletion of Rheb1 (Tubule-Rheb1-/-) was generated. Compared to control littermates, Tubule-Rheb1-/- mice were phenotypically normal within 2 months after birth but developed more severe kidney dysfunction, tubular cell death including apoptosis, necroptosis and ferroptosis, mitochondrial defect and less PGC-1α expression after cisplatin injection. In primary cultured tubular cells, Rheb1 ablation exacerbated cisplatin-induced cell death and mitochondrial defect. Furthermore, haploinsufficiency for Tsc1 in tubular cells led to Rheb1 activation and mitigated cisplatin-induced cell death, mitochondrial defect and AKI. Together, this study uncovers that Rheb1 may protect against cisplatin-induced tubular cell death and AKI through maintaining mitochondrial homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / drug therapy*
  • Acute Kidney Injury / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Death / drug effects*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cisplatin / pharmacology
  • Homeostasis / drug effects*
  • Homeostasis / physiology
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney Tubules / metabolism
  • Mice, Inbred C57BL
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Protective Agents / pharmacology
  • Ras Homolog Enriched in Brain Protein / metabolism*


  • Antineoplastic Agents
  • Protective Agents
  • Ras Homolog Enriched in Brain Protein
  • Rheb protein, mouse
  • Cisplatin