Role of Lysine-Specific Demethylase 1 in Angiotensin II-Induced Hypertensive Kidney Disease

Background: Hypertension is a major contributor to chronic kidney disease (CKD) and end-stage kidney disease. Angiotensin II (Ang II), a key effector of the renin-angiotensin system, promotes tubular injury, inflammation, and fibrosis. Epigenetic regulators such as lysine-specific demethylase 1 (LSD1) have emerged as important modulators of gene expression and cellular stress responses. However, the role of LSD1 in hypertensive kidney disease remains unclear. Methods: To investigate the function of LSD1 in hypertensive CKD, we utilized a tamoxifen-inducible LSD1 knockout mouse model. Mice were subjected to vehicle or Ang II infusion via osmotic minipumps. Kidney tissues were analyzed for histopathological changes, fibrotic, and molecular signaling pathways involved in cell cycle regulation and fibroblast activation. Cultured tubular epithelial cells and fibroblasts were used to investigate the role of LSD1 in regulating tubular epithelial cell dedifferentiation and fibroblast activation in vitro. Results: Ang II infusion induced LSD1 expression in tubular epithelial cells and myofibroblasts. LSD1-deficient mice exhibited protection against Ang II-induced kidney disease with reduced tubular damage. Further, LSD1-deficient mice displayed significant less inflammatory infiltration and fibrosis. Expression of fibrosis markers such as α-SMA, fibronectin, and collagen I was significantly reduced. Inflammatory cytokines including MCP-1 and IL-6 were considerably downregulated in LSD1-deficient mice following Ang II infusion. Additionally, LSD1 deficiency inhibited G2/M cell cycle arrest and suppressed activation of Smad3, a key profibrotic signaling. Conclusion: LSD1 plays a pathogenic role in Ang II-induced hypertensive kidney disease by promoting epithelial cell injury, inflammation, and fibrotic remodeling. Targeting LSD1 may provide a novel epigenetic-based therapeutic approach to limit CKD progression in patients with hypertension. Funding: NIDDK Support