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

Background: Acute kidney injury (AKI) is a significant clinical concern, especially in elderly patients, due to its high morbidity, mortality, and risk of progression to chronic kidney disease (CKD). Cellular senescence(definition) contributes to AKI and CKD pathogenesis and is considered a potential therapeutic target. Senolytics(definition), such as the combination of dasatinib and quercetin (D&Q), have shown beneficial effects in chronic disease models. However, their impact in AKI remains poorly understood. This study evaluates the effect of D&Q in an acute folic acid-induced nephropathy (FAN) mouse model. Methods: Male mice were pretreated with dasatinib (5 mg/kg) and quercetin (50 mg/kg) before induction of AKI using a single intraperitoneal injection of folic acid (125 mg/kg). Kidney function was assessed 48 hours post-injury by measuring serum creatinine and blood urea nitrogen (BUN). Renal gene expression of injury markers (Lcn2, Havcr1), the senescence marker Cdkn1a (p21), and SASP-related genes were quantified by qPCR. Immunohistochemistry was used to evaluate p21-positive cells and Klotho protein levels in kidney tissue. Results: D&Q treatment did not improve renal function following folic acid-induced injury. Creatinine and BUN levels were elevated similarly in both untreated and D&Q-treated FAN groups. D&Q pretreatment increased the expression of injury biomarkers (Lcn2, Havcr1), the senescence gene Cdkn1a, and multiple SASP components. The number of p21+ senescent cells remained unchanged between groups. Moreover, D&Q failed to prevent the folic acid-induced reduction in the anti-aging factor Klotho. Conclusion: Contrary to expectations, senolytic treatment with D&Q did not protect against folic acid-induced AKI and instead exacerbated markers of kidney damage and senescence. These findings highlight the complexity of targeting senescence in acute settings and suggest caution when considering the use of D&Q in AKI patients. Funding: Government Support – Non-U.S.