Recombinant GDF15 prophylaxis attenuates cardiorenal toxicity and fibrosis induced by doxorubicin and angiotensin II

Abstract

Anthracycline chemotherapy induces cardiotoxicity through mitochondrial damage and cell apoptosis that are exacerbated in vivo by angiotensin II (Ang II). Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine with protective functions but its capacity to mitigate doxorubicin (Dox)-induced cardiotoxicity and Ang II-associated cardiorenal stress remains unclear. Human embryonic stem cell-derived cardiomyocytes were used to evaluate Dox toxicity and to benchmark recombinant GDF15 against conventional dexrazoxane pretreatment. Cardiomyocyte viability, mitochondrial integrity and function, apoptosis, and transcriptome profiles by RNA sequencing were evaluated. To determine in vivo efficacy, C57BL/6 J mice were administered GDF15 (0.5 mg/kg, intraperitoneal) 24 h before once weekly Dox (5 mg/kg). Ang II was infused subcutaneously via surgically implanted osmotic pump. Mice were sacrificed for histopathologic analysis 1 week after the fourth cycle of Dox. In vitro, Dox-induced mitochondrial fragmentation, loss of membrane potential, transcriptional dysregulation, and apoptosis were significantly attenuated by recombinant GDF15 pretreatment, with efficacy comparable to dexrazoxane. Cytotoxic effects of daunorubicin on cardiomyocytes were also attenuated by GDF15. In vivo, Ang II, Dox, and Dox + Ang II induced cardiorenal injury characterized by hypertension, sarcomere disarray, myocardial and renal fibrosis, and glomerular, tubular, and perivascular abnormalities. GDF15 prophylaxis mitigated these pathologic changes, preserved myocardial and renal tissue architecture, and reduced cardiorenal fibrosis. Recombinant GDF15 pretreatment can protect the heart and kidneys from Dox-induced cardiorenal toxicity and Ang II-exacerbated injury. These findings encourage further investigation into GDF15 as a potential prophylaxis against cardiorenal toxicity associated with anthracycline chemotherapy and renin-angiotensin system activation.