Linagliptin and/or α-pinene attenuate cisplatin nephrotoxicity in rats via modulating phosphatase and tensin homolog-induced kinase 1/Parkin/microtubule-associated proteins 1A/1B light chain 3II/SQSTM1/sequestosome-1-assisted mitophagy.

Acute kidney injury is considered the most harmful and prevalent type of cisplatin-induced nephrotoxicity. In the current research, the potential prophylactic effects of linagliptin and/or α-pinene were investigated on cisplatin-induced functional, biochemical, and structural changes in rat kidneys. Forty Sprague-Dawley male rats were separated into five groups (n = 8): (1) normal group; (2) model group (cisplatin 7.5 mg/kg, i.p., single dose); (3) linagliptin group (3 mg/kg, p.o. for 18 days); (4) α-pinene group (50 mg/kg, p.o. for 18 days); and (5) linagliptin + α-pinene group (linagliptin 3 mg/kg + α-pinene 50 mg/kg, p.o.) for 18 days. Cisplatin was administered to all groups on day 15, excluding the normal group. Possible antioxidant, anti-inflammatory, and antiapoptotic activities were evaluated. In addition, mitophagy and mitochondrial biogenesis boosting mechanisms of both drugs were examined. Cisplatin administration produced a marked elevation in serum creatinine, urea, and renal kidney injury molecule-1 levels. Oxidative stress was markedly increased in the kidney homogenate. Similarly, cisplatin elevated renal inflammatory markers, activated the inflammasome, and increased apoptotic markers. It diminished mitophagy and mitochondrial biogenesis by reducing phosphatase and tensin homolog-induced kinase 1, Parkin, and peroxisome proliferator-activated receptor γ coactivator 1α levels. Contrarily, cisplatin raised microtubule-associated proteins 1A/1B light chain 3II and SQSTM1/sequestosome-1 levels. Coadministration of linagliptin and α-pinene demonstrated a potential prophylactic strategy in this preclinical model, likely through attenuation of oxidative stress, inflammation, apoptosis, and enhancement of mitophagy. However, this combination requires further validation in additional experimental models, including optimization of dosing regimens and evaluation of potential interactions with chemotherapy outcomes. SIGNIFICANCE STATEMENT: Linagliptin and/or α-pinene attenuate cisplatin-induced nephrotoxicity in rats by modulation of mitochondrial biogenesis and mitophagy.