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<p>Gentamicin (GM) is a key antibiotic for treating severe Gram-negative infections; however, its clinical utility is restricted by dose- and duration-dependent nephrotoxicity. This renal injury involves an interplay of oxidative stress, inflammation, and dysregulation of the RhoA/ROCK and AMPK/SIRT1/Nrf2 pathways. In this study, we evaluated the potential reno-protective effects of saxagliptin and calcitriol, administered individually and in combination, in a rat model. Forty adult male albino rats were divided into five groups: control, GM, GM + saxagliptin, GM + calcitriol, and GM + saxagliptin + calcitriol. GM administration caused marked renal dysfunction accompanied by oxidative imbalance, cytokine activation, suppression of AMPK/SIRT1/Nrf2 signalling, enhanced RhoA/ROCK activity, and histological damage with fibrosis. Treatment with either saxagliptin or calcitriol partially ameliorated these alterations, while combined therapy produced the most pronounced improvement, restoring renal function, enhancing antioxidant capacity, reducing inflammatory responses, normalizing molecular signalling, and preserving renal architecture. These findings demonstrate that the saxagliptin–calcitriol combination provides enhanced protection against GM-induced nephrotoxicity through RhoA/ROCK inhibition and AMPK/SIRT1/Nrf2 activation, proposing a promising dual-therapy strategy for mitigating GM-associated kidney injury.</p>

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Synergistic nephroprotection by saxagliptin and calcitriol against gentamicin-induced renal injury: integrated regulation of RhoA/ROCK and AMPK/SIRT1/Nrf2 signalling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Rania H. Shalaby,
  • Naglaa Raafat AbdRaboh,
  • M. Hussein,
  • Ayman Ahmed,
  • Batool Khan,
  • Hana Iqbal,
  • Isra Abbas,
  • Masiha Tasneem Banu,
  • Sabira Morbiwala,
  • Sarah Ragab Abd El-Khalik,
  • Nadia M. El Rouby

摘要

Gentamicin (GM) is a key antibiotic for treating severe Gram-negative infections; however, its clinical utility is restricted by dose- and duration-dependent nephrotoxicity. This renal injury involves an interplay of oxidative stress, inflammation, and dysregulation of the RhoA/ROCK and AMPK/SIRT1/Nrf2 pathways. In this study, we evaluated the potential reno-protective effects of saxagliptin and calcitriol, administered individually and in combination, in a rat model. Forty adult male albino rats were divided into five groups: control, GM, GM + saxagliptin, GM + calcitriol, and GM + saxagliptin + calcitriol. GM administration caused marked renal dysfunction accompanied by oxidative imbalance, cytokine activation, suppression of AMPK/SIRT1/Nrf2 signalling, enhanced RhoA/ROCK activity, and histological damage with fibrosis. Treatment with either saxagliptin or calcitriol partially ameliorated these alterations, while combined therapy produced the most pronounced improvement, restoring renal function, enhancing antioxidant capacity, reducing inflammatory responses, normalizing molecular signalling, and preserving renal architecture. These findings demonstrate that the saxagliptin–calcitriol combination provides enhanced protection against GM-induced nephrotoxicity through RhoA/ROCK inhibition and AMPK/SIRT1/Nrf2 activation, proposing a promising dual-therapy strategy for mitigating GM-associated kidney injury.