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KMID : 0620920220540050626
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Experimental & Molecular Medicine
2022 Volume.54 No. 5 p.626 ~ p.638
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Latrophilin-2 is a novel receptor of LRG1 that rescues vascular and neurological abnormalities and restores diabetic erectile function
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Yin Guo Nan
Kim Do-Kyun
Kang Ji-In
Im Ye-Bin
Lee Dong-Sun
Han Ah-Reum
Ock Ji-Yeon
Choi Min-Ji
Kwon Mi-Hye
Limanjaya Anita
Jung Saet-Byel
Yang Ji-Min
Min Kwang-Wook
Yun Jeong-Won
Koh Yong-Jun
Park Jong-Eun
Hwang Dae-Hee
Suh Jun-Kyu
Ryu Ji-Kan
Kim Ho-Min
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Abstract
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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 ?-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.
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KEYWORD
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Biological therapy, Cytokines, Extracellular signalling molecules, Recombinant protein therapy
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