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. 2025 Jul:234:72-85.
doi: 10.1016/j.freeradbiomed.2025.04.015. Epub 2025 Apr 12.

Intermedin protects peritubular capillaries by inhibiting eNOS uncoupling through AMPK/GTPCH-I/BH4 pathway and alleviate CKD following AKI

Hui Lin  1 , Juan Pan  1 , Junhua Zhang  1 , Yuyin He  1 , Yuan Ge  1 , Dan Niu  2 , Weixia Han  2 , Xiaoli Han  1 , Fan Li  1 , Xiaomei Bai  1 , Xinyuan Feng  1 , Ling Lin  1 , Ruihua Shen  1 , Xiaole Su  1 , Xi Qiao  3
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Free article

Intermedin protects peritubular capillaries by inhibiting eNOS uncoupling through AMPK/GTPCH-I/BH4 pathway and alleviate CKD following AKI

Hui Lin et al. Free Radic Biol Med. 2025 Jul.
Free article

Abstract

Background: Even after recovery of kidney function following AKI, progression to CKD may still occur, characterized by a reduction in peritubular capillaries (PTC) and subsequent kidney fibrosis. Reactive oxygen species (ROS) from uncoupled eNOS are suspected to damage endothelial cells and cause PTC rarefaction observed in AKI-CKD. Intermedin (IMD) inhibits eNOS uncoupling by activating AMPK, but its impact on AKI-CKD transition remains unclear.

Methods: We utilized IMD-deficient (IMD-/-) mice to explore its effects on AKI-CKD transition, PTC density, endothelial damage, and kidney ROS in a kidney ischemia/reperfusion injury (IRI) model. To elucidate its protective mechanism for PTCs, we subsequently investigated the effects of IMD on endothelial cells and ROS using a hypoxia/reoxygenation (HR) model with human umbilical vein endothelial cells (HUVECs). Finally, we investigated the influence of IMD on AMPK/GTPCH-I/BH4/eNOS to explore its mechanism in alleviating oxidative stress.

Results: Compared with IMD+/+ littermate sham controls, PTC density was significantly reduced in IMD-/- sham mice, with significantly increased oxidative stress. Post-AKI, both IMD+/+ and IMD-/- mice demonstrated substantial declines in kidney function and histology, along with significant fibrosis, PTC reduction, and heightened oxidative stress. Moreover, the severity of kidney damage in IMD-/- mice following AKI was considerably more pronounced than in IMD+/+ mice. HR significantly induced eNOS uncoupling and oxidative stress in HUVECs. Treatment with IMD effectively inhibited eNOS uncoupling and ROS production, achieving levels comparable to the antioxidant N-acetylcysteine. The inhibitory effect of IMD on eNOS uncoupling was abrogated when L-NAME was introduced after HR. HR significantly impaired AMPK activation, which could be reversed by IMD. Additional experiments with inhibitors of GTPCH-I and AMPK, and exogenous BH4, confirmed that IMD protects endothelial cells by activating AMPK/GTPCH-I/BH4, thereby inhibiting eNOS uncoupling and ROS production.

Conclusion: We concluded that IMD inhibits AKI-CKD transition by protecting endothelial cells of PTC via AMPK/GTPCH-I/BH4/eNOS pathway.

Keywords: AMPK; Acute kidney injury; Chronic kidney disease; GTPCH-I; Intermedin; eNOS.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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