Abstract
Target-specific treatment is not available for acute kidney injury (AKI). A novel erythropoietin-derived cyclic helix B surface peptide (CHBP) protects kidneys against AKI subjected to different causes. Herein, we investigated the transcriptional profile of renoprotection induced by CHBP and its potential synergistic effects with caspase-3 (an executing enzyme of apoptosis and inflammation) siRNA (CASP3siRNA) on ischemia/reperfusion (IR)-induced AKI. Utilizing a mouse model with renal bilateral 30-min ischemia and 48-h reperfusion, the renoprotective effects of a single dose of CHBP (24 nmol/kg) or CASP3siRNA (0.03 mg/kg) were demonstrated on renal function and structure, active 17 kDa caspase-3 and HMGB1 expression in IR kidneys. Combined treatment of CHBP and CASP3siRNA further preserved kidney structure, and reduced active caspase-3 and HMGB1. Furthermore, fold change > 1.414 and P < 0.05 were used to identify differentially expressed genes (DEGs). In IR kidneys, 281 DEGs induced by CHBP were mainly involved in promoting cell division and improving cellular function and metabolism (up-regulated STAT5B and SLC22A7). The additional administration of CASP3siRNA caused 504 and 418 DEGs in IR + CHBP kidneys with or without NCsiRNA, with 37 genes in common. These DEGs were associated with modulated apoptosis and inflammation (up-regulated BCL6,SLPI and SERPINA3M), and immunity, injury and microvascular homeostasis (up-regulated CFH and GREM1, and down-regulated ANGPTL2). This proof-of-effect study indicated that the synergistic renoprotection of CHBP and CASP3siRNA at the early stage of IR-induced AKI. Underlying genes, BCL6, SLPI, SERPINA3M, GREM1 and ANGPTL2, might be potential new biomarkers for clinical applications.
Significance Statement The synergistic renoprotection of erythropoietin derived peptide CHBP and siRNA targeting CASP3 was achieved by better preserved kidney structure and reduced injury mediator at the early stage of IR-induced AKI. The mechanistic study of gene profiling revealed more candidate genes such as BCL6, SLPI and SERPINA3M, associated with cell function, metabolism and immune response, might be potential new biomarkers of diagnosis and siRNA therapy for IR-induced AKI.
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