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

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(definition) has been described in AKI, CKD and ageing, and has been proposed as a promising therapeutic target. The senolytic drugs combination dasatinib plus quercetin (D&Q) is beneficial in some pathological conditions, including experimental CKD, but there is no data in AKI. Methods: The effect of D&Q treatment was tested in folic acid-induced nephrotoxicity (AKI-FAN), a murine AKI model. Results: D&Q pretreatment did not prevent renal dysfunction in the acute phase of AKI-FAN, as determined by serum creatinine and BUN levels at 48 hours. 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 anti-aging factor Klotho in damaged kidneys. Conclusions: D&Q treatment was not protective in AKI-FAN, exacerbating some deleterious responses. These results suggest caution when exploring the clinical translation of D&Q senolytic activity.