Störmer Johanna, Gwinner Wilfried, Derlin Katja, Immenschuh Stephan, Rong Song, Jang Mi-Sun, Shushakova Nelli, Haller Hermann, Gueler Faikah, Greite Robert
Nephrology, Hannover Medical School, 30625 Hannover, Germany.
Radiology, Hannover Medical School, 30625 Hannover, Germany.
Biomedicines. 2022 May 22;10(5):1198. doi: 10.3390/biomedicines10051198.
Nephrotoxic drugs can cause acute kidney injury (AKI) and analgesic nephropathy. Diclofenac is potentially nephrotoxic and frequently prescribed for pain control. In this study, we investigated the effects of single and repetitive oral doses of diclofenac in the setting of pre-existing subclinical AKI on the further course of AKI and on long-term renal consequences. Unilateral renal ischemia-reperfusion injury (IRI) for 15 min was performed in male CD1 mice to induce subclinical AKI. Immediately after surgery, single oral doses (100 mg or 200 mg) of diclofenac were administered. In a separate experimental series, repetitive treatment with 100 mg diclofenac over three days was performed after IRI and sham surgery. Renal morphology and pro-fibrotic markers were investigated 24 h and two weeks after the single dose and three days after the repetitive dose of diclofenac treatment using histology, immunofluorescence, and qPCR. Renal function was studied in a bilateral renal IRI model. A single oral dose of 200 mg, but not 100 mg, of diclofenac after IRI aggravated acute tubular injury after 24 h and caused interstitial fibrosis and tubular atrophy two weeks later. Repetitive treatment with 100 mg diclofenac over three days aggravated renal injury and caused upregulation of the pro-fibrotic marker fibronectin in the setting of subclinical AKI, but not in sham control kidneys. In conclusion, diclofenac aggravated renal injury in pre-existing subclinical AKI in a dose and time-dependent manner and already a single dose can cause progression to chronic kidney disease (CKD) in this model.
肾毒性药物可导致急性肾损伤（AKI）和镇痛剂肾病。双氯芬酸具有潜在肾毒性，常用于控制疼痛。在本研究中，我们调查了在已有亚临床AKI的情况下，单次和重复口服双氯芬酸对AKI进一步病程及长期肾脏后果的影响。对雄性CD1小鼠进行单侧肾缺血再灌注损伤（IRI）15分钟以诱导亚临床AKI。术后立即给予单次口服剂量（100毫克或200毫克）的双氯芬酸。在另一个实验系列中，IRI和假手术后，连续三天重复给予100毫克双氯芬酸治疗。在双氯芬酸单次给药后24小时和两周以及重复给药三天后，使用组织学、免疫荧光和qPCR研究肾脏形态和促纤维化标志物。在双侧肾IRI模型中研究肾功能。IRI后单次口服200毫克双氯芬酸（而非100毫克）在24小时后加重急性肾小管损伤，并在两周后导致间质纤维化和肾小管萎缩。在亚临床AKI情况下，连续三天重复给予100毫克双氯芬酸治疗会加重肾损伤并导致促纤维化标志物纤连蛋白上调，但在假手术对照肾脏中则不会。总之，双氯芬酸在已有亚临床AKI的情况下以剂量和时间依赖性方式加重肾损伤，在该模型中，单次给药即可导致进展为慢性肾脏病（CKD）。
