New Therapeutic Method for Alleviating Damage of Acute Kidney Injury Through BCL-2 Gene Promoter I-Motif.

Abstract

Acute kidney injury (AKI) is a global public health problem with its pathogenesis not fully understood. Excessive apoptosis of renal tubular epithelial cells is an important feature of AKI patients, and therefore an anti-apoptotic approach could be used in the treatment for AKI. Up-regulation of B-cell lymphoma-2 (BCL-2) gene and protein has been found to be correlated with anti-apoptosis of cells. It has been found that the presence of the C-rich sequence on the upstream region of the BCL-2 gene promoter could form DNA secondary i-motif structure, and its stabilization by small molecules could up-regulate gene transcription and translation. In the present study, we constructed AKI models through folic acid (FA) induction. With these in vitro and in vivo models, we demonstrated that the acridone derivative A22 could up-regulate the expression of BCL-2 by targeting its gene promoter i-motif to reduce renal tubular epithelial cell apoptosis and improve renal function in many ways. A22 could alleviate FA-induced oxidative stress injury, inflammatory response, and endoplasmic reticulum stress in mouse kidneys. Our results provided a potentially new anti-apoptotic approach for the treatment of early stages of AKI. Our employed model focused on its short-term effect on AKI, while its long-term efficacy and safety, particularly regarding the regeneration of renal tubular epithelial cells, require further investigation before clinical application. This study further demonstrated that promoter i-motif could be targeted for up-regulating BCL-2 expression for the treatment of important diseases caused by excessive apoptosis.