Comparative effects of incretin-based therapy on doxorubicin-induced nephrotoxicity in rats: the role of SIRT1/Nrf2/NF-κB/TNF-α signaling pathways.

Introduction: Nephrotoxicity represents a major complication of using doxorubicin (DOX) in the management of several types of cancers. Increased oxidative stress and the activation of inflammatory mediators play outstanding roles in the development of DOX-induced kidney damage. This study aimed to investigate whether the two pathways of incretin-based therapy, glucagon-like peptide-1 receptor agonist (presented as semaglutide, SEM) and dipeptidyl peptidase-4 inhibitor (presented as alogliptin, ALO), differentially protect against DOX-induced nephrotoxicity in rats and to clarify the underlying molecular mechanisms. Methods: Adult male rats were divided into six groups: control (received the vehicle), DOX (20 mg/kg, single I.P. on day 8), DOX + ALO (20 mg/kg/day, P.O. for 10 days), DOX + SEM (12 µg/kg/day, S.C. for 10 days), ALO-alone, and SEM-alone groups. At the end of the study, the animals were sacrificed and their kidney functions, oxidative stress, and inflammatory markers were assessed. Kidney sections were also subjected to histopathological examinations. Results: The co-treatment with either ALO or SEM manifested an improvement in the kidney functions, as evidenced by lower serum concentrations of creatinine, urea, and cystatin C compared to the DOX group. Lower levels of MDA, higher levels of GSH, and increased SOD activity were observed in either ALO- or SEM-treated groups than those observed in the DOX group. DOX administration resulted in decreased renal expressions of sirtuin 1 (SIRT1) and Nrf2 with increased NF-κB and TNF-α expressions, and these effects were ameliorated by treatment with either ALO or SEM. Discussion: Co-treatment with either ALO or SEM showed a renoprotective effect that was mediated by their antioxidant and anti-inflammatory effects via the SIRT1/Nrf2/NF-κB/TNF-α pathway. The fact that both pathways of the incretin-based therapy demonstrate an equally positive effect in alleviating DOX-induced renal damage is equally noteworthy.

Protective effect of empagliflozin on gentamicin-induced acute renal injury via regulation of SIRT1/NF-κB signaling pathway.

Gentamicin is a highly effective antibiotic. However, its major complication is nephrotoxicity. This study investigated the beneficial effects of empagliflozin against gentamicin-induced nephropathy. Kidney damage was induced in male Wistar rats by administration of gentamicin (100 mg/kg/day, i.p.) for 8 days. Two doses of empagliflozin (10 and 20 mg/kg, p.o.) were concomitantly given with gentamicin for 8 days. Gentamicin administration increased serum creatinine, urea, and cystatin C concentrations. Empagliflozin in both doses ameliorated these changes via mitigation of gentamicin-induced increase in renal oxidative stress, inflammation, and apoptosis. Empagliflozin added to GM treatment led to lower measured levels of TGF-B, NF-κB and caspase 3, and only the higher dose increased PAX2 levels indicating an improvement in tubular regeneration. Additionally, empagliflozin (20 mg/kg/day) markedly prevented gentamicin-induced histopathological changes. The protective effects of empagliflozin may be mediated by decreasing gentamicin concentration in renal tissue and possibly other effects like antioxidant and antiapoptotic effects.