Latrophilin-2 is a novel receptor of LRG1 that rescues vascular and neurological abnormalities and restores diabetic erectile function
1
조회
0
다운로드
4
인용
0
참고문헌
초록
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.
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.
참고문헌 (57)
- Kolluru, G. K., "Endothelial dysfunction and diabetes : effects on angiogenesis, vascular remodeling, and wound healing", Int. J. Vasc. Med, 2012, pp.918267~ (2012)
- Malavige, L. S., "Erectile dysfunction in diabetes mellitus", J. Sex. Med, 6, pp.1232~1247 (2009)
- Kim Soyeun, "Novel Emerging Therapies for Erectile Dysfunction", The World Journal of Men's Health, 39(1), pp.48~64 (2021), 대한남성과학회[DOI]
- Bennett, N. E., "Improvement in erectile dysfunction after neurotrophic factor gene therapy in diabetic rats", J. Urol, 173, pp.1820~1824 (2005)
- Burchardt, M., "Application of angiogenic factors for therapy of erectile dysfunction : protein and DNA transfer of VEGF 165 into the rat penis", Urology, 66, pp.665~670 (2005)
- Ghatak, K., "Dickkopf2 rescues erectile function by enhancing penile neurovascular regeneration in a mouse model of cavernous nerve injury", Sci. Rep, 7, pp.17819~ (2017)
- Hu, L., "Essential role of brain-derived neurotrophic factor(bdnf)in diabetic erectile dysfunction", Andrologia, 50, pp.e12924~ (2018)
- Jin, H. R., "Intracavernous delivery of a designed angiopoietin-1 variant rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse", Diabetes, 60, pp.969~980 (2011)
- Takahashi, N., "Periodicity of leucine and tandem repetition of a 24-amino acid segment in the primary structure of leucine-rich alpha 2-glycoprotein of human serum", Proc. Natl Acad. Sci. USA, 82, pp.1906~1910 (1985)
- Serada, S., "iTRAQ-based proteomic identification of leucine-rich alpha-2glycoprotein as a novel inflammatory biomarker in autoimmune diseases", Ann. Rheum. Dis, 69, pp.770~774 (2010)
- Serada, S., "Serum leucine-rich alpha-2 glycoprotein is a disease activity biomarker in ulcerative colitis", Inflamm. Bowel Dis, 18, pp.2169~2179 (2012)
- Watson, C. J., "Proteomic analysis of coronary sinus serum reveals leucine-rich alpha2-glycoprotein as a novel biomarker of ventricular dysfunction and heart failure", Circ. Heart Fail, 4, pp.188~197 (2011)
- Miyajima, M., "Leucine-rich alpha2-glycoprotein is a novel biomarker of neurodegenerative disease in human cerebrospinal fluid and causes neurodegeneration in mouse cerebral cortex", PLoS One, 8, pp.e74453~ (2013)
- Nakajima, M., "Leucine-rich alpha-2-glycoprotein is a marker for idiopathic normal pressure hydrocephalus", Acta Neurochir, 153, pp.1339~1346 (2011)
- Andersen, J. D., "Leucine-rich alpha-2-glycoprotein-1 is upregulated in sera and tumors of ovarian cancer patients", J. Ovarian Res, 3, pp.21~ (2010)
- Ladd, J. J., "Increased plasma levels of the APC-interacting protein MAPRE1, LRG1, and IGFBP2 preceding a diagnosis of colorectal cancer in women", Cancer Prev. Res, 5, pp.655~664 (2012)
- Okano, T., "Plasma proteomics of lung cancer by a linkage of multidimensional liquid chromatography and two-dimensional difference gel electrophoresis", Proteomics, 6, pp.3938~3948 (2006)
- Sandanayake, N. S., "A combination of serum leucine-rich alpha-2-glycoprotein 1, CA19-9 and interleukin-6 differentiate biliary tract cancer from benign biliary strictures", Br. J. Cancer, 105, pp.1370~1378 (2011)
- Pek, S. L., "Elevation of a novel angiogenic factor, leucine-rich-alpha2-glycoprotein(LRG1), is associated with arterial stiffness, endothelial dysfunction, and peripheral arterial disease in patients with type 2 diabetes", J. Clin. Endocrinol. Metab, 100, pp.1586~1593 (2015)
- Chen, C., "Elevated plasma and vitreous levels of leucine-rich-alpha2-glycoprotein are associated with diabetic retinopathy progression", Acta Ophthalmol, 97, pp.260~264 (2019)
- Liu, C., "A Multifunctional Role of Leucine-Rich-Alpha 2 Glycoprotein 1 in Cutaneous Wound Healing Under Normal and Diabetic Conditions", Diabetes, 69, pp.2467~2480 (2020)
- Li, W., "Leucine-rich alpha-2-glycoprotein-1 promotes diabetic corneal epithelial wound healing and nerve regeneration via regulation of matrix metalloproteinases", Exp. Eye Res, 196, pp.108060~ (2020)
- Gao, Y., "LRG1 Promotes Keratinocyte Migration and Wound Repair through Regulation of HIF-1alpha Stability", J. Invest. Dermatol, 140, pp.455~464 (2020)
- Choi, C. H., "LRG1 is an adipokine that promotes insulin sensitivity and suppresses inflammation", Elife, 8(11), pp.e81559~ (2022)[DOI]
- Wang, X., "LRG1 promotes angiogenesis by modulating endothelial TGF-beta signalling", Nature, 499, pp.306~311 (2013)
- Yin, G. N., "The pericyte as a cellular regulator of penile erection and a novel therapeutic target for erectile dysfunction", Sci. Rep, 5, pp.10891~ (2015)
- Neng, L., "Isolation and culture of endothelial cells, pericytes and perivascular resident macrophage-like melanocytes from the young mouse ear", Nat. Protoc, 8, pp.709~720 (2013)
- Yin, G. N., "Matrigel-based sprouting endothelial cell culture system from mouse corpus cavernosum is potentially useful for the study of endothelial and erectile dysfunction related to high-glucose exposure", J. Sex. Med, 9, pp.1760~1772 (2012)
- Detaille, D., "Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process", Diabetes, 54, pp.2179~2187 (2005)
- Jin, H. R., "Functional and morphologic characterizations of the diabetic mouse corpus cavernosum: comparison of a multiple low-dose and a single highdose streptozotocin protocols", J. Sex. Med, 6, pp.3289~3304 (2009)
- Lee, M. J., "Identification of human complement factor B as a novel biomarker candidate for pancreatic ductal adenocarcinoma", J. Proteome Res, 13, pp.4878~4888 (2014)
- Bellacen, K., "Aortic ring assay", J. Vis. Exp, 33, pp.1564~ (2009)
- Yin, G. N., "Establishment of in vitro model of erectile dysfunction for the study of high-glucose-induced angiopathy and neuropathy", Andrology, 5, pp.327~335 (2017)
- Frei, A. P., "Ligand-based receptor identification on living cells and tissues using TRICEPS", Nat. Protoc, 8, pp.1321~1336 (2013)
- Sugita, S., "alpha-Latrotoxin receptor CIRL", latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors. G-protein coupling not required for triggering exocytosis, 1998, pp.273, 32715~32724
- Moreno-Salinas, A. L., "Latrophilins: A Neuro-Centric View of an Evolutionary Conserved Adhesion G Protein-Coupled Receptor Subfamily", Front. Neurosci, 13, pp.700~ (2019)
- Nieberler, M., "Control of Adhesion GPCR Function Through Proteolytic Processing", Handb. Exp. Pharmacol, 234, pp.83~109 (2016)
- Talakatta, G., "Diabetes induces fibrotic changes in the lung through the activation of TGF-beta signaling pathways", Sci. Rep, 8, pp.11920~ (2018)
- Gumy, L. F., "Hyperglycaemia inhibits Schwann cell proliferation and migration and restricts regeneration of axons and Schwann cells from adult murine DRG", Mol. Cell Neurosci, 37, pp.298~311 (2008)
- Yin, G. N., "Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse", Proc. Natl Acad. Sci. USA, 111, pp.E2731~2740 (2014)
- Jorgensen, C., "Cell-specific information processing in segregating populations of Eph receptor ephrin-expressing cells", Science, 326, pp.1502~1509 (2009)
- Doyle, S. E., "Latrophilin-2 is a novel component of the epithelialmesenchymal transition within the atrioventricular canal of the embryonic chicken heart", Dev. Dyn, 235, pp.3213~3221 (2006)
- Lee, C. S., "Identification of Latrophilin-2 as a Novel Cell-Surface Marker for the Cardiomyogenic Lineage and Its Functional Significance in Heart Development", Circulation, 139, pp.2910~2912 (2019)
- Anderson, G. R., "Postsynaptic adhesion GPCR latrophilin-2 mediates target recognition in entorhinal-hippocampal synapse assembly", J. Cell Biol, 216, pp.3831~3846 (2017)
- Chen, D., "Developmental Perspectives on Arterial Fate Specification", Front. Cell. Dev. Biol, 9, pp.691335~ (2021)
- Carmeliet, P., "Common mechanisms of nerve and blood vessel wiring", Nature, 436, pp.193~200 (2005)
- Zacchigna, S., "Neurovascular signalling defects in neurodegeneration", Nat. Rev. Neurosci, 9, pp.169~181 (2008)
- Taniguchi, K., "NF-kappaB, inflammation, immunity and cancer : coming of age", Nat. Rev. Immunol, 18, pp.309~324 (2018)
- Gutierrez, H., "Regulation of neural process growth, elaboration and structural plasticity by NF-kappaB", Trends Neurosci, 34, pp.316~325 (2011)
- Grosjean, J., "Vascular endothelial growth factor signalling in endothelial cell survival : a role for NFkappaB", Biochem. Biophys. Res. Commun, 340, pp.984~994 (2006)
- Gur, S., "Review of erectile dysfunction in diabetic animal models", Curr. Diabetes Rev, 10, pp.61~73 (2014)
- Danaei, G., "National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants", Lancet, 378, pp.31~40 (2011)
- Liu, J. J., "Plasma Leucine-Rich alpha-2-Glycoprotein 1 Predicts Rapid eGFR Decline and Albuminuria Progression in Type 2 Diabetes Mellitus", J. Clin. Endocrinol. Metab, 102, pp.3683~3691 (2017)
- Hong, Q., "LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-beta-Induced Angiogenesis", J. Am. Soc. Nephrol, 30, pp.546~562 (2019)
- Zhang, X., "Leucine-rich alpha-2-glycoprotein predicts proliferative diabetic retinopathy in type 2 diabetes", J. Diabetes Complications, 33, pp.651~656 (2019)
- Druhan, L. J., "Leucine Rich alpha-2 Glycoprotein : A Novel Neutrophil Granule Protein and Modulator of Myelopoiesis", PLoS One, 12, pp.e0170261~ (2017)
- Zhang, J., "LRG1 modulates epithelial-mesenchymal transition and angiogenesis in colorectal cancer via HIF-1alpha activation", J. Exp. Clin. Cancer Res, 35, pp.29~ (2016)
