Latrophilin-2 is a novel receptor of LRG1 that rescues vascular and neurological abnormalities and restores diabetic erectile function

Yin, Guo Nan; Kim, Do-Kyun; Kang, Ja Heon; Im, Yebin; Lee, Dong Sun; Han, Ah‐Reum; Ock, Jiyeon; Choi, Min‐Ji; Kwon, Mi‐Hye; Limanjaya, Anita; Jung, Sungyup; Yang, Jimin; Min, Kwang Wook; Yun, Jeongwon; Koh, Yongjun; Park, Jong-Eun; Hwang, Daehee; Suh, Jun‐Kyu; Ryu, Ji‐Kan; Kim, Ho Min

doi:10.1038/s12276-022-00773-5

Cited by 21 publications

(41 citation statements)

References 57 publications

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“…Twelve weeks after completing STZ injections (after induction), mice with a tail vein blood glucose level > 300 mg/dL and exhibiting a significant body weight reduction were considered to have DM. Fasting and postprandial blood glucose levels were determined using an Accu-Check blood glucose meter (Roche Diagnostics, Mannheim, Germany) [18].…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Functional and Immunofluorescence Evaluations of Vascular and Neural Integrities in Urinary Bladder of Streptozotocin-Induced Diabetic Mice

Kwon¹,

Choi

Liu

et al. 2022

Int Neurourol J

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Purpose: To assess functional and structural changes in vascular and neural structures associated with diabetic bladder dysfunction (DBD) in the bladders of streptozotocin (STZ)-induced diabetic mice.Methods: Eight-week-old C57BL/6 mice were injected with STZ at 50 mg/kg daily for 5 consecutive days. Catheters were inserted 12 weeks later, and 5 days after catheter placement bladder functions were assessed by conscious cystometry. Neurovascular and extracellular matrix marker changes in harvested urinary bladders were investigated by immunofluorescent staining. Body weights and fasting and postprandial blood glucose levels were measured 12 weeks after STZ injection.Results: STZ-induced diabetic mice had significantly lower body weights and significantly higher blood glucose levels. Assessment of bladder function in STZ-induced diabetic mice revealed a nearly 3-fold increase in bladder capacity and intercontractile interval compared to controls. However, basal pressure, maximal bladder pressure, and threshold pressure were not significantly different. Morphological and structural analysis showed that STZ-induced diabetic mice had significantly reduced microvascular density in lamina propria (33% of the nondiabetic control values), and severely decreased nerve contents in the detrusor region (42% of the nondiabetic control values).Conclusions: STZ-induced diabetic mice exhibit functional and structural derangements in urinary bladder. The present study provides a foundation and describes a useful means of evaluating the efficacies of therapeutic targets and exploring the detailed mechanism of DBD.

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Section: Animals and Treatmentsmentioning

confidence: 99%

Functional and Immunofluorescence Evaluations of Vascular and Neural Integrities in Urinary Bladder of Streptozotocin-Induced Diabetic Mice

Kwon¹,

Choi

Liu

et al. 2022

Int Neurourol J

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“…Recombinant human LRG1 protein and human LPHN2 variants protein (Lec, Olf, Lec/Olf domain, or ectodomain full) were expressed and puri ed as described previously 20 . LRG1 N-glycan mutants (N79D, N186D, N269D, and N325D) were constructed using the QuikChange Lightning Site-Directed Mutagenesis kit (#210518, Agilent Technologies) with the LRG1-Fc construct as a template.…”

Section: Recombinant Protein Expression and Puri Cationmentioning

confidence: 99%

“…Recently, we reported that adhesion GPCR latrophilin-2 (LPHN2) is a TGF-β-independent receptor of LRG1, and the LRG1/LPHN2 axis exerts both angiogenic and neurotrophic effects under hyperglycemic conditions 20 . Given that the secreted LRG1 can be differently glycosylated and alterations in sugar chains may in uence the function of LRG1 in cancer 41,42 , we questioned the functional signi cance of LRG1's Nglycans on the LRG1/LPHN2 axis.…”

Section: De-glycosylation Of Lrg1 Enhances the Binding A Nity Towards...mentioning

confidence: 99%

“…2D-2F). As PI3K, AKT, and NF-κB p65 signalling constitute the key signalling pathway for LRG1/LPHN2-mediated angiogenesis and neurite outgrowth under hyperglycemic conditions 20 , we next compared these signalling pathways upon treatment of HUVECs and DRG with native LRG1 or DG-LRG1. Consistent with the above phenotypic outcomes, DG-LRG1 robustly increased the phosphorylation level of PI3K, AKT, and NF-κB under normal glucose conditions, and the phosphorylation of these signalling components upon treatment with DG-LRG1 was markedly reduced by shRNA-mediated LPHN2 knockdown (Fig.…”

Section: De-glycosylation Of Lrg1 Enhances the Binding A Nity Towards...mentioning

confidence: 99%

“…The pathophysiological mechanism underlying diabetic ED re ects endothelial dysfunction and autonomic neuropathy 43,44 . We previously reported that intracavernous delivery of recombinant LRG1 restores erectile function in the STZ-induced diabetic mouse by enhancing endothelial and cavernous nerve regeneration 20 . To test the potent e cacy of DG-LRG1 and LRG1 N325D, we measured ICP upon electrical stimulation of the cavernous nerve in diabetic mice after intracavernous injection of DG-LRG1 or LRG1 N325D.…”

Section: N325 Is a Crucial Glycosylation Site For Attenuating Lrg1 Fu...mentioning

confidence: 99%

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Crystal structure of LRG1 and the functional significance of LRG1’s glycan for LPHN2 activation

Kim

Yang²,

Yin

et al. 2022

Preprint

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The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1), primarily produced by hepatocytes and neutrophils, is a multifunctional protein that can modulate various signalling cascades, mainly TGFβ signalling. Serum LRG1 and neutrophil-derived LRG1 have different molecular weights due to differences in glycosylation, but what impact the differential glycan composition in LRG1 has on its cellular function is largely unknown. We previously reported that LRG1 can promote both angiogenic and neurotrophic processes under hyperglycemic conditions by interacting with LPHN2. Here, we determined the crystal structure of LRG1, identifying the horseshoe-like solenoid structure of LRG1 and its four N-glycosylation sites. In addition, our biochemical and cell-biological analysis found that de-glycosylation of LRG1, particularly the removal of glycans on N325, is critical for high-affinity binding of LRG1 to LPHN2, thereby promoting LRG1/LPHN2-mediated angiogenic and neurotrophic processes in mouse tissue explants, even under normal glucose conditions. Moreover, intracavernous administration of de-glycosylated LRG1 in a diabetic mouse model ameliorated vascular and neurological abnormalities and restored erectile function. Collectively, these data indicate a novel role of LRG1’s glycans as molecular switches that can tune the range of LRG1’s cellular functions, particularly the LRG1/LPHN2 signalling axis.

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Bezafibrate alleviates diabetes-induced spermatogenesis dysfunction by inhibiting inflammation and oxidative stress

Mu,

Luo,

et al. 2024

Heliyon

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Latrophilin-2 is a novel receptor of LRG1 that rescues vascular and neurological abnormalities and restores diabetic erectile function

Cited by 21 publications

References 57 publications

Functional and Immunofluorescence Evaluations of Vascular and Neural Integrities in Urinary Bladder of Streptozotocin-Induced Diabetic Mice

Functional and Immunofluorescence Evaluations of Vascular and Neural Integrities in Urinary Bladder of Streptozotocin-Induced Diabetic Mice

Crystal structure of LRG1 and the functional significance of LRG1’s glycan for LPHN2 activation

Bezafibrate alleviates diabetes-induced spermatogenesis dysfunction by inhibiting inflammation and oxidative stress

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