Latrophilin-2 is a novel receptor of LRG1

May 13, 2022

Intro

Latrophilin-2 is a novel receptor of LRG1 that rescues vascular and neurological abnormalities and restores diabetic erectile function - Diabetes mellitus (DM) is a chronic metabolic disorder that involves endothelial dysfunction and neuropathy and can lead to multiple complications, including cardiovascular disease, stroke, chronic kidney disease, foot ulcers, and retinopathy1. DM is also a major cause of erectile dysfunction (ED), which is a manifestation of microangiopathy and neuropathy1. Approximately 50–75% of male diabetic patients have ED2. Phosphodiesterase type 5 (PDE5) inhibitors are the most commonly used first-line treatment options for ED; however, these agents are ineffective in ~30% of patients and ultimately cannot rescue angiopathy and neuropathy in diabetic ED patients3. Tested alternative therapeutic options for ED include various angiogenic or neurotrophic factors, such as COMP-Ang1, vascular endothelial growth factor (VEGF), dickkopf2, neurotrophin-3 (NT3), and brain-derived neurotrophic factor (BDNF)4,5,6,7,8; however, these treatments have shown limited success in clinical trials.

Experimental & Molecular Medicine volume 54, pages626–638 (2022) Cite this article PDF  and Link to the nature.com

Abstract

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by inappropriate hyperglycemia, which causes endothelial dysfunction and peripheral neuropathy, ultimately leading to multiple complications. One prevalent complication is diabetic erectile dysfunction (ED), which is more severe and more resistant to treatment than nondiabetic ED. The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1) is a modulator of TGF-β-mediated angiogenesis and has been proposed as a biomarker for a variety of diseases, including DM. Here, we found that the adhesion GPCR latrophilin-2 (LPHN2) is a TGF-β-independent receptor of LRG1. By interacting with LPHN2, LRG1 promotes both angiogenic and neurotrophic processes in mouse tissue explants under hyperglycemic conditions. Preclinical studies in a diabetic ED mouse model showed that LRG1 administration into the penile tissue, which exhibits significantly increased LPHN2 expression, fully restores erectile function by rescuing vascular and neurological abnormalities. Further investigations revealed that PI3K, AKT, and NF-κB p65 constitute the key intracellular signaling pathway of the LRG1/LPHN2 axis, providing important mechanistic insights into LRG1-mediated angiogenesis and nerve regeneration in DM. Our findings suggest that LRG1 can be a potential new therapeutic option for treating aberrant peripheral blood vessels and neuropathy associated with diabetic complications, such as diabetic ED

Author

Guo Nan Yin, Do-Kyun Kim2, Ji In Kang Yebin Im Dong Sun Lee Ah-reum Han Jiyeon Ock Min-Ji Choi Mi-Hye Kwon Anita Limanjaya Saet-Byel Jung Jimin Yang2 Kwang Wook Min Jeongwon Yun Yongjun Koh Jong-Eun Park Daehee Hwang Jun-Kyu Suh, Ji-Kan Ryu and Ho Min Kim