Octreotide mitigates cisplatin-induced nephrotoxicity through coordinated modulation of the miR-34a/SIRT1 axis and downstream apoptotic, inflammatory, and fibrotic pathways.

Aims

Cisplatin (CIS) is a widely used chemotherapeutic agent, but its clinical utility is limited by dose-dependent nephrotoxicity. Octreotide (OCT), a somatostatin analog, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties in several experimental models, yet its therapeutic potential against cisplatin-induced nephrotoxicity remains largely unexplored. This study, therefore, investigated the nephroprotective potential and the underlying molecular mechanisms of octreotide against cisplatin- induced nephrotoxicity, and asked whether protection depends on the timing of administration. MATERIAL AND

Methods

Rats were allocated into five groups: Normal control (NC); OCT control (82.5 μg/kg, intramuscularly); CIS (a single intraperitoneal injection of 7 mg/kg); peri-treatment OCT was administered 7 days before and continued 14 days following cisplatin administration; and post-treatment OCT was initiated after cisplatin administration and continued for 14 days). KEY

Findings

Octreotide significantly improved renal function, attenuated tubular injury, and preserved renal histoarchitecture following cisplatin administration. These protective effects were associated with preservation of renal SSTR2 expression, suppression of cisplatin-induced miR-34a upregulation, and restoration of SIRT1 expression. This molecular response coincided with attenuation of p53-mediated apoptosis, enhancement of Nrf2/HO-1-dependent antioxidant defenses, inhibition of NF-κB-induced inflammation, restoration of IL-6-associated reparative responses, and suppression of TGF-β1/α-SMA-mediated profibrotic signaling, with the peri-treatment protocol consistently outperforming post-treatment.

Significance

Octreotide, particularly the peri-treatment protocol, confers significant protection against cisplatin-induced nephrotoxicity and is associated with coordinated modulation of the SSTR2/miR-34a/SIRT1 signaling axis and its downstream cytoprotective pathways, supporting its potential repurposing as a nephroprotective adjunct to cisplatin-based chemotherapy.