dianas 14(1) > Battaglia-Vieni etal

dianas | Vol 14 Num 1 | marzo 2025 | e202503x003

Combined Dasatinib and Quercetin treatment does not protect kidney damage in acute Folic-acid induced nephropathy.

Antonio Battaglia-Vieni^a, Lucia Tejedor-Santamaría, Vanessa Marchant, Sandra Rayego-Mateos, Fatima Milhano-Santos, Marta Ruiz-Ortega

Universidad Autónoma de Madrid.

a. antonio.battaglia@estudiante.uam.es

X Congreso de Señalización Celular, SECUAH 2024.
XIX Simposio de Dianas Terapéuticas.
17 a 21 de marzo, 2025. Universidad de Alcalá. Alcalá de Henares, Madrid. España.

Keywords: Renal damage; senescence; senolytic drugs and SASP

Abstract

Acute kidney injury (AKI) refers to a variety of pathological conditions with high morbidity and mortality, in which renal function is acutely compromised. AKI is a leading cause of death in hospitalized patients. To date, the kidney replacement therapy (hemodialysis or peritoneal dialysis) are the standard of care. Due to the lack of pharmacological strategies, AKI can also progress to Chronic Kidney Disease (CKD). Activation of cellular senescence is a mechanism shared by AKI and CKD. Senescence consists of the loss of the cell’s ability to divide, but with the metabolism still active, allowing cells to release a secretome called the “senescence-associated secretory phenotype” (SASP) containing proinflammatory cytokines, growth factors and chemokines. One of the potential strategies to target senescence are senolytic drugs that selectively eliminate senescent cells. Dasatinib and Quercetin (DQ), a mixture of an anticancer agent and a flavonoid was the first senolytic drug reported to induce apoptosis and ameliorate age-associated diseases. DQ has been tested in several human clinical trials in various pathologies, even in chronic kidney disease (NCT02848131). However, there is a lack of preclinical studies in AKI context. Therefore, our aim was to investigate the effect of DQ treatment in experimental AKI caused by folic acid nephrotoxicity (AKI-FAN). To this end, DQ (dasatinib; 5 mg/kg and quercetin; 50 mg/kg by oral gavage) was administered 24 h prior to FA administration (125 mg/kg; intraperitoneal injection) and mice were sacrificed 48 h later. Determination of serum and renal biomarkers of kidney injury showed no protective effect of DQ treatment in AKI-FAN, as indicated by a slight increase in serum urea and creatinine, and a significant increase in BUN in response to senolytic treatment. DQ also significantly increased renal gene expression levels of Lcn2 and Havcr1 compared to untreated AKI-FAN mice. Moreover, the evaluation of the tubular damage biomarker KIM-1 by immunohistochemistry showed that positive tubular KIM-1 staining in AKI-FAN was not prevented by DQ. Finally, the senolytic potential of DQ was also tested. The number of p21-positive cells in AKI-FAN was not change in response to DQ. Accordingly, gene expression of Cdkn1a and Ccl2, a SASP gene, significantly increased by DQ. Furthermore, the downregulation of the anti-aging factor Klotho induced by AKI-FAN was not reversed by DQ. Necroptosis related markers were also evaluated in AKI-FAN, DQ neither improved nor worsened them. Our data show that DQ does not have a protective effect in AKI, but further studies in additional mouse models are needed.