Ahram Canadian University

Doxorubicin (Dox) is a cornerstone chemotherapeutic agent whose clinical use is limited by nephrotoxicity driven by oxidative stress, renin-angiotensin system (RAS) imbalance, activation of the profibrotic Wnt/β-catenin pathway, and suppression of the renoprotective protein α-Klotho. Substance P (SP) signaling through the neurokinin-1 (NK-1) receptor is a mediator of inflammatory injury; however, its role in Dox-induced nephrotoxicity remains unexplored. Therefore, we investigated whether pharmacological blockade of the NK-1 receptor with MK-0869 could alleviate Dox-induced nephrotoxicity and modulate α-Klotho-associated antioxidant and signaling pathways. Male Sprague-Dawley rats were assigned to control, MK-0869, Dox, and Dox + MK-0869 groups. Dox nephrotoxicity was induced cumulatively (16 mg/kg over 28 days), while MK-0869 was administered orally (10 mg/kg/day). Renal function markers, signaling and oxidative stress markers were assessed using ELISA, qRT-PCR, Western blotting, immunohistochemistry, and histopathological analysis. MK-0869 markedly attenuated Dox-induced renal injury, significantly improving renal function and histological architecture. Specifically, compared with Dox-treated rats, MK-0869 reduced serum creatinine by 53% (p < 0.0001) while restoring renal α-Klotho levels nearly two-fold (p < 0.0001). Mechanistically, NK-1 receptor blockade suppressed SP signaling, restored Ang-(1-7) levels while attenuating the Ang II/AT-1 receptor axis, activated the Nrf2/HO-1 antioxidant pathway, reinstated FoxO3a-dependent SOD2 expression, and inhibited Wnt-1/β-catenin signaling, thereby reducing renal fibrosis. In conclusion, NK-1 receptor blockade confers robust protection against Dox-induced nephrotoxicity through integrated modulation of α-Klotho signaling, RAS balance, oxidative stress, and profibrotic pathways. These findings support MK-0869 as a promising renoprotective adjunct during Dox therapy and warrant further studies to evaluate long-term safety and translational potential.