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This study has been funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union through the projects; RICORS2040-RENAL; RD21/0005/0002, RD21/0005/0005, RD24/0004/0001, RD24/0004/0021, RD24/0004/0028, RD24/0004/0020; PI23/00394, PI24/00007, PI22/00469 and Miguel Servet CP23/00025 (to S. R-M). Other grants: PIPF-2023/SAL-GL-29648 (to A.B.-V) and INNOREN "P2022/BMD-7221: Nuevas estrategias diagnosticas y terapeuticas en enfermedad renal cronica" to M.R.O funded by Comunidad de Madrid.

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Dasatinib and Quercetin Combination Increased Kidney Damage in Acute Folic Acid-Induced Experimental Nephropathy

Publicated to:PHARMACEUTICALS 18 (6): 822- - 2025-05-30 18(6), DOI: 10.3390/ph18060822

Authors: Battaglia-Vieni, Antonio; Marchant, Vanessa; Tejedor-Santamaria, Lucia; Garcia-Caballero, Cristina; Flores-Salguero, Elena; Ruiz-Torres, Maria Piedad; Rayego-Mateos, Sandra; Sanz, Ana Belen; Ortiz, Alberto; Ruiz-Ortega, Marta

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Abstract

Background/Objectives: Acute kidney injury (AKI) remains an unsolved medical problem due to the lack of effective treatments, high mortality, and increased susceptibility to progression to chronic kidney disease (CKD), especially in the elderly. Cellular senescence has been described in AKI, CKD, and aging and has been proposed as a promising therapeutic target. The senolytic drug combination of dasatinib plus quercetin (D&Q) is beneficial in some pathological conditions, including experimental CKD, but there are no data for AKI. Methods: The effect of D&Q combination was tested in folic acid-induced nephrotoxicity (FAN-AKI), a murine AKI model. Results: D&Q pretreatment did not prevent renal dysfunction in the acute phase of FAN-AKI, as determined by serum creatinine and BUN levels at 48 h. Moreover, gene expression of the kidney damage biomarkers Lcn2 and Havcr1, the Cdkn1a gene, which encodes p21, and some genes encoding components of the senescent cell secretome were significantly increased in response to D&Q treatment. The number of senescent p21-positive cells in injured kidneys was similar in untreated or D&Q-treated FAN mice. In addition, D&Q did not prevent the downregulation of the antiaging factor Klotho in damaged kidneys. Conclusions: D&Q treatment was not protective in FAN-AKI, exacerbating some deleterious responses. These results suggest caution when exploring the clinical translation of D&Q senolytic activity.

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