Intaermedin attenuates chronic intermittent hypoxia-induced renal fibrosis via SIRT1-mediated inhibition of the NOX4/ROS axis.

Obstructive sleep apnea hypopnea syndrome (OSAHS) is characterized by chronic intermittent hypoxia (CIH) and is an independent risk factor for chronic kidney disease (CKD); the underlying mechanism may involve oxidative stress. This study investigated the role of intermedin (IMD), a small antioxidant peptide, in CIH-induced renal fibrosis using complementary in vivo and in vitro models. Systemic IMD knockout (IMD-/-) mice and wild-type (IMD+/+) littermates were subjected to CIH for 12 weeks. Human proximal tubular epithelial cell (HK-2) was exposed to CIH for 48 h with or without exogenous IMD. Adeno-associated virus serotype 9 (AAV9)-mediated short hairpin RNA (shRNA) knockdown of NADPH oxidase 4 (NOX4) was performed in IMD-/- mice, and the selective sirtuin 1 (SIRT1) inhibitor EX527 was used in HK-2 cells. We showed that CIH upregulated IMD and its receptors (calcitonin receptor-like receptor [CLR] and receptor activity-modifying proteins [RAMPs]) in both mouse kidneys and HK-2 cells. IMD deficiency exacerbated CIH-induced renal dysfunction, fibrosis, oxidative stress, apoptosis, and inflammation, whereas exogenous IMD attenuated these pathological changes. Mechanistically, IMD upregulated SIRT1 and suppressed NOX4 expression. NOX4 knockdown in IMD-/- mice partially reversed the aggravated renal injury and fibrosis. In HK-2 cells, EX527 abolished the IMD-induced downregulation of NOX4 and its protective effects against CIH-induced reactive oxygen species (ROS) production, apoptosis, and collagen deposition, indicating that IMD inhibits NOX4 in a SIRT1-dependent manner. Collectively, these findings demonstrate that IMD mitigates CIH-induced renal fibrosis by upregulating SIRT1 and subsequently inhibiting the NOX4/ROS axis. This study identifies IMD as an endogenous renoprotective factor and suggests the SIRT1/NOX4/ROS pathway as a potential therapeutic target for OSAHS-associated nephropathy.