Abstract Fri110: Renal Tubular Mitochondrial AKT1 Improves Cardiac Function in Cardiovascular-Kidney-Metabolic Syndrome

Cardiovascular-kidney-metabolic (CKM) syndrome, affecting over 30% of adults, drives significant morbidity through interconnected cardiovascular, renal, and metabolic dysfunction. Renal proximal tubular mitochondria play a pivotal role in CKM by succumbing to dysfunction under metabolic stress, leading to oxidative damage, tubular injury, and systemic effects that exacerbate cardiac dysfunction. We investigated whether enhancing renal tubular mitochondrial AKT1 could improve cardiac outcomes. We used KMioxCAKT mice, a novel transgenic strain harboring inducible, mitochondria-targeting, constitutively active AKT1 (mcaAKT1) driven by a renal proximal tubule-specific promoter, treated with tamoxifen or corn oil and fed a high-fat diet for 16 weeks. With unchanged BUN or creatinine, tamoxifen-induced mice had significantly reduced proteinuria, urinary KIM-1, glomerulosclerosis, and fibrosis. Metabolic dysfunction was markedly alleviated, with significant reductions in fasting glucose levels, improved glucose tolerance across 15-120 minutes post-glucose load, decreased fasting insulin levels, and enhanced insulin sensitivity as reflected by a reduced HOMA-IR. Echocardiography revealed improved cardiac function in tamoxifen-induced mice, with elevated ejection fraction (72.2%-73.6% vs. 45.1%-66.4%), increased fractional shortening (35.8%-37.1% vs. 30.4%-46.9%), and reduced left ventricular wall thickness (0.08-0.13 cm vs. 0.12-0.14 cm), collectively indicating attenuated cardiac hypertrophy. These findings suggest that enhancing renal tubular mitochondrial AKT1 could ameliorate the pathophysiology of CKM syndrome through improved cardiac systolic function, highlighting a potential therapeutic target for cardiorenal protection.