Alternative splicing as a novel pathogenic mechanism in chronic kidney disease

Chronic kidney disease (CKD) is a progressive condition with incompletely understood pathogenesis, affecting over 10 % of the global population. The poor understanding of these mechanisms impedes therapeutic development, leaving current treatments largely ineffective at halting or reversing disease progression. The balance between damage and repair in renal tubular epithelial cells, the primary renal parenchymal cells, is pivotal to CKD progression, and excessive damage to these cells significantly contributing to tubular atrophy and renal fibrosis. Recent studies leveraging single-cell sequencing reveal disease-associated dynamics and molecular drivers in renal tubular epithelial cells, with findings suggesting that alternative splicing (AS) represents a novel pathogenic mechanism in CKD. This review focuses on the regulatory mechanisms of AS and its documented and emerging roles in CKD pathogenesis. Certain CKD driver molecules can globally regulate AS, while key CKD marker genes are prone to generating functionally distinct splice isoforms. In addition, the pathogenic mechanism of many familial kidney disease patients is gene mutation leading to abnormal splicing. This review aims to elucidate the functional link between AS and CKD, highlighting AS-targeting approaches as a potential therapeutic strategy. However, future research should further investigate the dynamics of AS and its regulators in CKD, and delineate their functional contributions.