Molecular and cellular endocrinology · 2026
Repeated low-dose streptozotocin induces latent renal proximal tubular injury independently of blood glucose.
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Nakamura Masashi, Nakai Kunihiro, Tsujinaka-Sawai Erika, Kurose Ryo, Tanaka Hisaya, Umehara Minato, Sawai Shinji, Yamamoto Satomi, Minamida Atsushi, Yamauchi-Sawada Hiroko, Sunahara Yasuto, Matoba Yayoi, Nakamura Itaru, Yamashita Noriyuki, Kamezaki Michitsugu, Kirita Yuhei, Tamagaki Keiichi, Matoba Satoaki, Kusaba Tetsuro
Аннотация
INTRODUCTION: Streptozotocin (STZ) is transported into pancreatic β-cells and renal proximal tubular epithelial cells via GLUT2, where it induces DNA damage. Although repeated low-dose (RLD) STZ administration is widely used to induce diabetes while minimizing toxicity, its renal effects remain underexplored.
AIM: To determine whether RLD STZ causes proximal tubular injury and whether sodium-glucose cotransporter 2 (SGLT2) inhibition mitigates such damage.
METHODOLOGY: Male mice received a single high dose (150 mg/kg) or RLD STZ (50 mg/kg/day for five days). Some mice were pretreated with an SGLT2 inhibitor. Renal and pancreatic tissues were analyzed for DNA damage, tubular injury, and membrane transporter expression.
RESULTS: Both regimens induced DNA damage in renal proximal tubules and pancreatic islets, reducing the expression of tubular membrane transporters. SGLT2 inhibitor pretreatment attenuated tubular injury under the RLD regimen but did not affect islet DNA damage or diabetes incidence. Nevertheless, transporter expression in proximal tubules was preserved.
CONCLUSION: Both single high dose and RLD STZ administration induces proximal tubular injury and subsequent reduction of membrane transporter expression. SGLT2 inhibitor pretreatment mitigates latent STZ-induced tubular injury but does not influence diabetes onset. The interpretation of results on type 1 diabetic nephropathy using RLD STZ administration should consider the potential presence of tubular epithelial cell injury.
AIM: To determine whether RLD STZ causes proximal tubular injury and whether sodium-glucose cotransporter 2 (SGLT2) inhibition mitigates such damage.
METHODOLOGY: Male mice received a single high dose (150 mg/kg) or RLD STZ (50 mg/kg/day for five days). Some mice were pretreated with an SGLT2 inhibitor. Renal and pancreatic tissues were analyzed for DNA damage, tubular injury, and membrane transporter expression.
RESULTS: Both regimens induced DNA damage in renal proximal tubules and pancreatic islets, reducing the expression of tubular membrane transporters. SGLT2 inhibitor pretreatment attenuated tubular injury under the RLD regimen but did not affect islet DNA damage or diabetes incidence. Nevertheless, transporter expression in proximal tubules was preserved.
CONCLUSION: Both single high dose and RLD STZ administration induces proximal tubular injury and subsequent reduction of membrane transporter expression. SGLT2 inhibitor pretreatment mitigates latent STZ-induced tubular injury but does not influence diabetes onset. The interpretation of results on type 1 diabetic nephropathy using RLD STZ administration should consider the potential presence of tubular epithelial cell injury.