Cardiorenal Syndrome Type 1: Activation of Dual Apoptotic Pathways

Abstract

Cardiorenal syndrome type 1 (CRS1) pathophysiology is complex, and immune-mediated damage, including alterations in the immune response with monocyte apoptosis and cytokine release, has been reported as a potential mechanism. In this study, we examined the putative role of renal tubular epithelial cell (RTC) apoptosis as a pathogenic mechanism in CRS1. In particular, we investigated the caspase pathways involved in induced apoptosis. We enrolled 29 patients with acute heart failure (AHF), 11 patients with CRS1, and 15 controls (CTR) without AHF or acute kidney injury (AKI). Patients who had AKI prior to the episode of AHF or who had any other potential causes of AKI were excluded. Plasma from different groups was incubated with RTCs for 24 h. Subsequently, cell apoptosis, DNA fragmentation, and caspase-3, -8, and -9 activities were investigated in RTCs incubated with AHF, CRS1, and CTR plasma. A p value <0.5 was considered statistically significant. A quantitative analysis of apoptosis showed significantly higher apoptosis rates in CRS1 patients compared to AHF patients and CTR (p < 0.01). This increase in apoptosis was strongly confirmed by caspase-3 levels (ρ = 0.73). Caspase-8 and -9 were significantly higher in CRS1 patients compared to AHF patients and CTR (p < 0.01). Furthermore, caspase-3 levels showed a significantly positive correlation with caspase-8 (ρ = 0.57) and -9 (ρ = 0.47; p < 0.001). This study demonstrated the significantly heightened presence of dual apoptotic disequilibrium in CRS1. Our findings indicated that apoptosis may have a central role in the mechanism of CRS1, and it could be a potential therapeutic target in this syndrome.