title: 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.
authors.affiliation: Department of Nephrology, Dialysis and Transplantation, Vicenza, Italy ; Department of IRRIV-International Renal Research Institute Vicenza, Vicenza, Italy ; Department of Information Engineering, University of Padua, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pastori
authors.affiliation: Department of Nephrology, Dialysis and Transplantation, Vicenza, Italy ; Department of IRRIV-International Renal Research Institute Vicenza, Vicenza, Italy.
authors.forename: Grazia Maria
authors.initials: GM
authors.lastname: Virzì
authors.affiliation: Department of Nephrology, Dialysis and Transplantation, Vicenza, Italy ; Department of IRRIV-International Renal Research Institute Vicenza, Vicenza, Italy ; Department of Medicine DIMED, University of Padua Medical School, Padua, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Brocca
authors.affiliation: Department of Nephrology, Dialysis and Transplantation, Vicenza, Italy ; Department of IRRIV-International Renal Research Institute Vicenza, Vicenza, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: de Cal
authors.affiliation: Nephrology, Dialysis and Kidney Transplantation Unit, Department of Medical Sciences, University of Torino, Azienda Ospedaliera 'Città della Salute e della Scienza di Torino-Presidio Molinette', Torino, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cantaluppi
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Castellani
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Italy.
authors.forename: Marny
authors.initials: M
authors.lastname: Fedrigo
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Thiene
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Valente
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Angelini
authors.affiliation: Department of Internal Medicine, San Bortolo Hospital, Vicenza, Italy ; Internal Medicine Unit, Sant'Antonio Hospital Padua, Padua, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Vescovo
authors.affiliation: Department of Nephrology, Dialysis and Transplantation, Vicenza, Italy ; Department of IRRIV-International Renal Research Institute Vicenza, Vicenza, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ronco
keywords: Acute kidney injury; Apoptosis; Cardiorenal syndromes; Caspase; Renal tubular cells