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Background <p>Renal fibrosis is a key contributor to chronic kidney disease progression. The TGF-β1/Smad signaling pathway, particularly Smad2 and Smad3 mediate pro-fibrotic responses, while Smad7 exerts inhibitory effects.</p> Aim <p>The study aimed to evaluate the therapeutic potential of paraxanthine (Para), an active caffeine metabolite, and azilsartan (Azil), an angiotensin II receptor blocker, in attenuating gentamicin (GM)-induced renal fibrosis through targeting Smad pathway and miRNA-21/200b.</p> Methods <p>Seventy male albino mice were randomized into seven groups (<i>n</i> = 10): Control, GM, SIS3 + GM, Para + GM, Azil + GM, Para + SIS3 + GM, and Azil + SIS3 + GM. GM (40 mg/kg, I.P.) was administered daily for 7 days. Subsequently, Para (20.5 mg/kg) and Azil (5 mg/kg) were given orally, while SIS3 (2 mg/kg, I.P.) was administered for 7 days. Serum and urine renal function markers were measured. Renal histopathology, protein expression of TGF-β1, CTGF, Smad3, Smad2 and Smad7, and gene expression of miRNA-21 and miRNA-200b were evaluated.</p> Results <p>GM caused significant (<i>p</i> &lt; 0.001) nephrotoxicity with elevated BUN, serum creatinine, urinary albumin/creatinine ratio, and KIM-1 and increased fibrosis and marked type I collagen deposition compared to normal control. However, treatments with Para &amp; Azil resulted in significant (<i>p</i> &lt; 0.05) improvement in renal functions. Pro-fibrotic markers TGF-β1, connective tissue growth factor (CTGF), Type I Collagen, Smad 2 and Smad3 were reduced, while Smad7 was increased in treated groups <i>versus</i> GM group. Additionally, miRNA-21 was downregulated and miRNA-200b was upregulated following treatments.</p> Conclusion <p>Paraxanthine and azilsartan demonstrated significantl restoring of kidney function and suppressing fibrotic progression. Their actions were mediated through regulation of Smad3/7 signaling and modulation of miRNA-21 and miRNA-200b expression, highlighting these pathways as promising therapeutic targets for the treatment of renal fibrosis.</p>

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Paraxanthine and azilsartan attenuate gentamicin-induced renal fibrosis via modulation of TGF-β1/Smad3/7 signaling and miRNA-21/miRNA-200b expression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月11日

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  • Nany Saad Rizk El-Adwy,
  • Nahla E. El-Ashmawy,
  • Ghada M. Al-Ashmawy,
  • Naglaa F. Khedr

摘要

Background

Renal fibrosis is a key contributor to chronic kidney disease progression. The TGF-β1/Smad signaling pathway, particularly Smad2 and Smad3 mediate pro-fibrotic responses, while Smad7 exerts inhibitory effects.

Aim

The study aimed to evaluate the therapeutic potential of paraxanthine (Para), an active caffeine metabolite, and azilsartan (Azil), an angiotensin II receptor blocker, in attenuating gentamicin (GM)-induced renal fibrosis through targeting Smad pathway and miRNA-21/200b.

Methods

Seventy male albino mice were randomized into seven groups (n = 10): Control, GM, SIS3 + GM, Para + GM, Azil + GM, Para + SIS3 + GM, and Azil + SIS3 + GM. GM (40 mg/kg, I.P.) was administered daily for 7 days. Subsequently, Para (20.5 mg/kg) and Azil (5 mg/kg) were given orally, while SIS3 (2 mg/kg, I.P.) was administered for 7 days. Serum and urine renal function markers were measured. Renal histopathology, protein expression of TGF-β1, CTGF, Smad3, Smad2 and Smad7, and gene expression of miRNA-21 and miRNA-200b were evaluated.

Results

GM caused significant (p < 0.001) nephrotoxicity with elevated BUN, serum creatinine, urinary albumin/creatinine ratio, and KIM-1 and increased fibrosis and marked type I collagen deposition compared to normal control. However, treatments with Para & Azil resulted in significant (p < 0.05) improvement in renal functions. Pro-fibrotic markers TGF-β1, connective tissue growth factor (CTGF), Type I Collagen, Smad 2 and Smad3 were reduced, while Smad7 was increased in treated groups versus GM group. Additionally, miRNA-21 was downregulated and miRNA-200b was upregulated following treatments.

Conclusion

Paraxanthine and azilsartan demonstrated significantl restoring of kidney function and suppressing fibrotic progression. Their actions were mediated through regulation of Smad3/7 signaling and modulation of miRNA-21 and miRNA-200b expression, highlighting these pathways as promising therapeutic targets for the treatment of renal fibrosis.