Zoledronic acid aggravates kidney damage during ischemia reperfusion injury in rat

J Environ Pathol Toxicol Oncol. 2015;34(1):53-61. doi: 10.1615/jenvironpatholtoxicoloncol.2015012424.


Introduction: Zoledronic acid (ZA), a bisphosphonate, increases the levels of cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), and reactive oxygen species (ROS) in subjects without cancer. Increased production of ROS, TNF-α, and IL-6 during ischemia and reperfusion (I/R) injury stimulates apoptosis that leads to renal injury. We aimed to investigate whether ZA treatment has a protective effect on renal tissues during I/R.

Materials and methods: Twenty-four Sprague-Dawley rats were used in this study, and they were subdivided randomly into three groups, each containing eight rats. Infrarenal abdominal aortic cross ligation was performed on the I/R group. After 2 h of ischemia, 2 h of reperfusion was applied. A single dose of 100 µg/kg ZA was administered intraperitoneally to the ZA group. I/R was performed after 48 h.

Results: Whereas TNF-α, IL-6, and nitric oxide (NO) levels of the I/R group were higher than those of the control group, TNF-α, IL-6, and NO levels of the ZA group were higher than those of the I/R group [TNF-α (p=0.038), IL-6 (p=0.012), NO (p=0.002), and caspase-3 (p=0.037)] and the control group [TNF-α (p<0.001), IL-6 (p<0.001), NO (p<0.001), and caspase-3 (p<0.001)]. Whereas the carbonic anhydrase II (CA-II) level of the ZA group was lower than that of the control group (p=0.040), the CA-II level of the I/R group was higher than that of the control group (p=0.020).

Conclusion: ZA may aggravate renal injury during I/R by increasing cytokine production and apoptosis. It may also increase renal injury and metabolic acidosis during I/R by suppressing CA-II enzyme activities.

MeSH terms

  • Animals
  • Bone Density Conservation Agents / toxicity*
  • Carbonic Anhydrase II / analysis
  • Carbonic Anhydrase II / antagonists & inhibitors
  • Diphosphonates / toxicity*
  • Imidazoles / toxicity*
  • Interleukin-6 / analysis
  • Kidney / blood supply
  • Kidney / drug effects*
  • Kidney / pathology
  • Male
  • Nitric Oxide / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / pathology*
  • Tumor Necrosis Factor-alpha / analysis
  • Zoledronic Acid


  • Bone Density Conservation Agents
  • Diphosphonates
  • Imidazoles
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Zoledronic Acid
  • Carbonic Anhydrase II