Streptozotocin induces renal proximal tubular injury through p53 signaling activation

Streptozotocin (STZ), an anti-cancer drug that is primarily used to treat neuroendocrine tumors (NETs) in clinical settings, is incorporated into pancreatic beta-cells or proximal tubular epithelial cells through the glucose transporter, GLUT2. However, its cytotoxic effects on kidney cells have been underestimated and the underlying mechanisms remain unclear. We herein demonstrated that DNA damage and subsequent p53 signaling were responsible for the development of STZ-induced tubular epithelial injury. We detected tubular epithelial DNA damage in NET patients treated with STZ. Unbiased transcriptomics of STZ-treated tubular epithelial cells in vitro showed the activation of the p53 signaling pathway. STZ induced DNA damage and activated p53 signaling in vivo in a dose-dependent manner, resulting in reduced membrane transporters. The pharmacological inhibition of p53 and sodium-glucose transporter 2 (SGLT2) mitigated STZ-induced epithelial injury. However, the cytotoxic effects of STZ on pancreatic beta-cells were preserved in SGLT2 inhibitor-treated mice. The present results demonstrate the proximal tubular-specific cytotoxicity of STZ and the underlying mechanisms in vivo. Since the cytotoxic effects of STZ against beta-cells were not impaired by dapagliflozin, pretreatment with an SGLT2 inhibitor has potential as a preventative remedy for kidney injury in NET patients treated with STZ.

Automated summary

Streptozotocin (STZ) is an anti-cancer drug used to treat neuroendocrine tumors (NETs). It enters pancreatic beta-cells or proximal tubular epithelial cells through GLUT2. This study demonstrated the cytotoxic effects of STZ on kidney cells and identified DNA damage and p53 signaling as underlying mechanisms. Inhibition of p53 and SGLT2 mitigated kidney injury caused by STZ, but the cytotoxic effects on pancreatic beta-cells were not affected. These findings suggest the potential use of SGLT2 inhibitors as preventive treatments for kidney injury in NET patients treated with STZ.