Angiopoietin 2 and Neuropeptide Y are Associated with Diabetic Kidney
                    Disease in Type 1 Diabetes Mellitus

Jelizaveta Sokolovska; Juris Stefanovics; Gita Gersone; Leonora Pahirko; Janis Valeinis; Sanita Kalva-Vaivode; Vita Rovite; Leons Blumfelds; Valdis Pirags; Peteris Tretjakovs

doi:10.1055/a-1079-4711

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2020; 128(10): 654-662
DOI: 10.1055/a-1079-4711

Article

Angiopoietin 2 and Neuropeptide Y are Associated with Diabetic Kidney Disease in Type 1 Diabetes Mellitus

Jelizaveta Sokolovska

¹Faculty of Medicine, University of Latvia, Riga, Latvia

,

Juris Stefanovics

¹Faculty of Medicine, University of Latvia, Riga, Latvia

,

Gita Gersone

²Faculty of Medicine, Department of Human Physiology and Biochemistry, Riga Stradins University, Latvia

,

Leonora Pahirko

⁴Faculty of Physics, Mathematics and Optometry, University of Latvia, Riga, Latvia

,

Janis Valeinis

⁴Faculty of Physics, Mathematics and Optometry, University of Latvia, Riga, Latvia

,

Sanita Kalva-Vaivode

¹Faculty of Medicine, University of Latvia, Riga, Latvia

,

Vita Rovite

⁵Latvian Biomedical Research and Study Centre, Riga, Latvia

,

Leons Blumfelds

²Faculty of Medicine, Department of Human Physiology and Biochemistry, Riga Stradins University, Latvia

,

Valdis Pirags

¹Faculty of Medicine, University of Latvia, Riga, Latvia

³Pauls Stradins Clinical University Hospital, Riga, Latvia

⁵Latvian Biomedical Research and Study Centre, Riga, Latvia

,

Peteris Tretjakovs

²Faculty of Medicine, Department of Human Physiology and Biochemistry, Riga Stradins University, Latvia

› Author Affiliations

Abstract

Background Serum angiopoietin 2 levels have been associated with endothelial dysfunction and diabetic kidney disease. Derangements in autonomous nervous system lead to increased production of vasoconstrictory and angiogenic mediators such as norepinephrine and neuropeptide Y and are associated with increased risk of microvascular complications.

Aim To investigate associations between angiopoietin 2, neuropeptide Y and diabetic kidney disease in patients with type 1 diabetes mellitus.

Methods 289 patients with type 1 diabetes mellitus duration > 1 year were included. Patients were stratified according to presence of diabetic nephropathy (macroalbuminuria, estimated glomerular filtration rate<60 ml/min/1.73 m² or end-stage renal disease). Angiopoietin 2 was measured by Luminex technology. Neuropeptide Y was measured by ELISA.

Results Patients with diabetic nephropathy had significantly increased levels of angiopoietin 2 (4020.5 (2172.4–5778.1) pg/ml vs. 2001.0 (1326.7–2862.7) pg/ml) and neuropeptide Y (18.22 (14.85–21.85) ng/ml vs. 12.91 (9.96–17.07) ng/ml). Higher levels of angiopoietin 2 and neuropeptide Y were observed also in patients with arterial hypertension. Angiopoietin 2 and neuropeptide Y correlated significantly (ρ=0.245, p<0.001). Both biomarkers were significant predictors of estimated glomerular filtration rate and diabetic nephropathy in univariate regression models. In the fully adjusted regression models and after application of a stepwise selection regression method, angiopoietin 2 demonstrated a stronger predictive power for diabetic nephropathy compared to neuropeptide Y.

Conclusion Diabetic nephropathy is associated with increased serum concentrations of angiopoietin 2 (marker of endothelial dysfunction) and neuropeptide Y (marker of sympathetic activity) in type 1 diabetes. Angiopoietin 2 is a more potent predictor of diabetic nephropathy compared to neuropeptide Y.

Keywords

type 1 diabetes - diabetic nephropathy - arterial hypertension - estimated glomerular filtration rate - endothelial dysfunction, autonomic neuropathy

Full Text

References

References
1 Davies MJ, D'Alessio DA, Fradkin J. et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018; 41: 2669-2701
2 Tuttle KR, Bakris GL, Bilous RW. et al. Diabetic kidney disease: A report from an ADA Consensus Conference. Am J Kidney Dis 2014; 64: 510-533
3 Brownlee M. The pathobiology of diabetic complications: A unifying mechanism. Diabetes 2005; 54: 1615-1625
4 Gnudi L. Angiopoietins and diabetic nephropathy. Diabetologia 2016; 59: 1616-1620 doi:10.1007/s00125-016-3995-3
5 Kim JA, Montagnani M, Koh KK. et al. Reciprocal relationships between insulin resistance and endothelial dysfunction: Molecular and pathophysiological mechanisms. Circulation 2006; 113: 1888-1904
6 Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007; 87: 315-424
7 Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev 2013; 93: 137-188
8 Isidori AM, Venneri MA, Fiore D. Angiopoietin-1 and Angiopoietin-2 in metabolic disorders: Therapeutic strategies to restore the highs and lows of angiogenesis in diabetes. J Endocrinol Invest 2016; 39: 1235-1246 doi:10.1007/s40618-016-0502-0
9 Lim HS, Blann AD, Chong AY. et al. Plasma vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 in diabetes: Implications for cardiovascular risk and effects of multifactorial intervention. Diabetes Care 2004; 27: 2918-2924
10 Khairoun M, de Koning EJ, van den Berg BM. et al. Microvascular damage in type 1 diabetic patients is reversed in the first year after simultaneous pancreas-kidney transplantation. Am J Transplant 2013; 13: 1272-1281
11 Li L, Qian L, Yu ZQ. Serum angiopoietin-2 is associated with angiopathy in type 2 diabetes mellitus. J Diabetes Complications 2015; 29: 568-571 doi:10.1016/j.jdiacomp.2015.02.006
12 El-Asrar MA, Elbarbary NS, Ismail EA. et al. Circulating angiopoietin-2 levels in children and adolescents with type 1 diabetes mellitus: Relation to carotid and aortic intima-media thickness. Angiogenesis 2016; 19: 421-431
13 David S, John SG, Jefferies HJ. et al. Angiopoietin-2 levels predict mortality in CKD patients. Nephrol Dial Transplant 2012; 27: 1867-1872
14 Saharinen P, Alitalo K. The yin, the yang, and the angiopoietin-1. J Clin Invest 2011; 121: 2157-2159 doi:10.1172/jci58196
15 Chang FC, Chiang WC, Tsai MH. et al. Angiopoietin-2-induced arterial stiffness in CKD. J Am Soc Nephrol 2014; 25: 1198-1209
16 Tsai YC, Lee CS, Chiu YW. et al. Angiopoietin-2, renal deterioration, major adverse cardiovascular events and all-cause mortality in patients with diabetic nephropathy. Kidney Blood Press Res 2018; 43: 545-554
17 Shroff RC, Price KL, Kolatsi-Joannou M. et al. Circulating angiopoietin-2 is a marker for early cardiovascular disease in children on chronic dialysis. PLoS One 2013; 8: e56273
18 Orlov S, Cherney DZ, Pop-Busui R. et al. Cardiac autonomic neuropathy and early progressive renal decline in patients with nonmacroalbuminuric type 1 diabetes. Clin J Am Soc Nephrol 2015; 10: 1136-1144
19 Sheng Y, Zhu L. The crosstalk between autonomic nervous system and blood vessels. Int J Physiol Pathophysiol Pharmacol 2018; 10: 17-28
20 Gordin D, Groop PH. Aspects of hyperglycemia contribution to arterial stiffness and cardiovascular complications in patients with type 1 diabetes. Journal of Diabetes Science and Technology 2016; 10: 1059-1064 doi:10.1177/1932296816636894
21 Yi M, Li H, Wu Z. et al. A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans. Cell Physiol Biochem 2018; 45: 88-107
22 Lurbe E, Redon J, Kesani A. et al. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 2002; 347: 797-805
23 Spallone V, Ziegler D, Freeman R. et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011; 27: 639-653
24 Dafaalla MD, Nimir MN, Mohammed MI. et al. Risk factors of diabetic cardiac autonomic neuropathy in patients with type 1 diabetes mellitus: A meta-analysis. Open heart 2016; 3: e000336
25 Tahrani AA, Dubb K, Raymond NT. et al. Cardiac autonomic neuropathy predicts renal function decline in patients with type 2 diabetes: A cohort study. Diabetologia 2014; 57: 1249-1256
26 Perin PC, Maule S, Quadri R. Sympathetic nervous system, diabetes, and hypertension. Clin Exp Hypertens 2001; 23: 45-55 doi:10.1081/ceh-100001196
27 Grassi G, Mark A, Esler M. The sympathetic nervous system alterations in human hypertension. Circ Res 2015; 116: 976-990 doi:10.1161/circresaha.116.303604
28 Vanhoutte PM, Shimokawa H, Tang EH. et al. Endothelial dysfunction and vascular disease. Acta physiologica (Oxford, England) 2009; 196: 193-222
29 Koulu M, Movafagh S, Tuohimaa J. et al. Neuropeptide Y and Y2-receptor are involved in development of diabetic retinopathy and retinal neovascularization. Ann Med 2004; 36: 232-240
30 Zoccali C, D'Arrigo G, Leonardis D. et al. Neuropeptide Y and chronic kidney disease progression: a cohort study. Nephrol Dial Transplant 2018; 33: 1805-1812
31 Suneja M, Murry DJ, Stokes JB. et al. Hormonal regulation of energy-protein homeostasis in hemodialysis patients: An anorexigenic profile that may predispose to adverse cardiovascular outcomes. Am J Physiol Endocrinol Metab 2011; 300: E55-E64
32 Satoh C, Satoh F, Takahashi K. et al. Elevated plasma immunoreactive neuropeptide Y concentrations and its increased urinary excretion in patients with advanced diabetic nephropathy. Endocr J 1999; 46: 139-146
33 Jaakkola U, Kakko T, Seppala H. et al. The Leu7Pro polymorphism of the signal peptide of neuropeptide Y (NPY) gene is associated with increased levels of inflammatory markers preceding vascular complications in patients with type 2 diabetes. Microvasc Res 2010; 80: 433-439
34 Jaakkola U, Pesonen U, Vainio-Jylha E. et al. The Leu7Pro polymorphism of neuropeptide Y is associated with younger age of onset of type 2 diabetes mellitus and increased risk for nephropathy in subjects with diabetic retinopathy. Exp Clin Endocrinol Diabetes 2006; 114: 147-152
35 Zoccali C, Mallamaci F, Tripepi G. et al. Prospective study of neuropeptide y as an adverse cardiovascular risk factor in end-stage renal disease. J Am Soc Nephrol 2003; 14: 2611-2617
36 Testa A, Mallamaci F, Macri R. et al. Neuropeptide Y receptor Y2 gene polymorphism interacts with plasma neuropeptide Y levels in predicting left ventricular hypertrophy in dialysis patients. J Hypertens 2010; 28: 1745-1751
37 Akagi S, Nagake Y, Sugimoto T. et al. Plasma neuropeptide Y concentrations in patients on hemodialysis. Nephron 2002; 92: 333-338
38 Levey AS, Stevens LA, Schmid CH. et al. A New Equation to Estimate Glomerular Filtration Rate. Ann Intern Med 2009; 150: 604-612
39 Chen S, Li H, Zhang C. et al. Urinary angiopoietin-2 is associated with albuminuria in patients with type 2 diabetes mellitus. Int J Endocrinol 2015; 2015: 163120
40 Parving HH, Persson F, Rossing P. Microalbuminuria: a parameter that has changed diabetes care. Diabetes Res Clin Pract 2015; 107: 1-8 doi:10.1016/j.diabres.2014.10.014
41 Rasul S, Reiter MH, Ilhan A. et al. Circulating angiopoietin-2 and soluble Tie-2 in type 2 diabetes mellitus: A cross-sectional study. Cardiovasc Diabetol 2011; 10: 55
42 El Karim IA, Linden GJ, Irwin CR. et al. Neuropeptides regulate expression of angiogenic growth factors in human dental pulp fibroblasts. J Endod 2009; 35: 829-833