open access

Vol 8, No 5 (2019)
ORIGINAL ARTICLES
Published online: 2019-08-26
Get Citation

Disturbances in angiogenesis and vascular maturation in the skin are associated with diabetic kidney disease in type 1 diabetes

Anna Adamska, Stanisław Piłaciński, Dorota Zozulińska-Ziółkiewicz, Agnieszka Gandecka, Agata Grzelka, Aneta Konwerska, Agnieszka Malińska, Michał Nowicki, Aleksandra Araszkiewicz
DOI: 10.5603/DK.2019.0019
·
Clinical Diabetology 2019;8(5):231-237.

open access

Vol 8, No 5 (2019)
ORIGINAL ARTICLES
Published online: 2019-08-26

Abstract

Introduction. The skin, as one of the most accessible tissues, is frequently used for investigations of microcirculation and angiogenesis. The aim of this study was to assess the relationship between the dermal microvessel density (MVD) and maturity and the presence of diabetic kidney disease (DKD) in adults with type 1 diabetes (T1D). Skin as the most accessible organ served as a model for the study of angiogenesis. Materials and methods. 148 consecutive T1D patients (87 men), median age of 41 [interquartile range (IQR): 31–49] years and diabetes duration of 21 (17–30) years, participated in the study. The patients were under the care of the Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences. Diabetic kidney disease was diagnosed in patients with increased albuminuria and at least 10-year duration of diabetes or evidence of diabetic retinopathy. The skin biopsy was performed on distal part of lower leg, using a sterile, disposable 3 mm biopsy punch with plunger (Disposable Biopsy Punches, Integra™ Miltex®). In the immunohistochemical analyses, we used: anti-CD133, anti-CD34, anti-CD31, and anti-von Willebrand factor (vWF) autoantibodies. Microvessel density measurement in all specimens was performed using “hot spots technique”. Slides were scanned using the MiraxMidi scanner (Carl Zeiss) and were viewed using CaseViewer (3DHISTECH Ltd. Budapest, Hungary). Data were analyzed using Statistica v. 13 software. Results. In the study group 21 patients with diagnosis DKD+, as compared to 127 subjects withaout DKD–, had longer duration of diabetes [30 (IQR: 21–36) vs. 21 (16–28) years, p = 0.002], higher prevalence of hypertension [14 (67%) vs. 37 (29%), p = 0.002], lower estimated glomerular filtration rate (eGFR) [66 (55–88) vs. 94 (83–106) mL/min/1.73 m2, p < 0.001]. Median MVD compared between groups with and without DKD, was similar for CD34+ vessels/1 mm2 [123 (100–170) vs. 121 (100–170), p = 0.775], CD133+ vessels/1 mm2 [79 (50–100) vs. 79 (63–93), p = 0.823], and for CD31+ vessels/ 1 mm2 [29 (21–46) vs. 38 (17–58), p = 0.454]. Median MVD vWF+ vessels/1 mm2 was lower in the group with than without DKD: 42 (25–54) vs. 54 (43–71), p = 0.009. The values given above were calculated for both layers of the dermis (papillary and reticular dermis). In multivariate logistic regression analysis presence of diabetic kidney disease was associated with lower median vWF+ MVD [odds ratio: 0.97 (95% confidence interval: 0.95–0.99), p = 0.017], with adjustment for age, gender, eGFR value, diabetes duration and presence of hypertension. MVD did not differ significantly between chronic kidney disease stages. Conclusion. In patients with type 1 diabetes and diabetic kidney disease the disturbances in the angiogenesis and vascular maturation are present. The number of mature blood vessels (vWF+) in the skin is reduced. Disturbances in the angiogenesis occur at early stages of diabetic kidney disease.

Abstract

Introduction. The skin, as one of the most accessible tissues, is frequently used for investigations of microcirculation and angiogenesis. The aim of this study was to assess the relationship between the dermal microvessel density (MVD) and maturity and the presence of diabetic kidney disease (DKD) in adults with type 1 diabetes (T1D). Skin as the most accessible organ served as a model for the study of angiogenesis. Materials and methods. 148 consecutive T1D patients (87 men), median age of 41 [interquartile range (IQR): 31–49] years and diabetes duration of 21 (17–30) years, participated in the study. The patients were under the care of the Department of Internal Medicine and Diabetology, Poznan University of Medical Sciences. Diabetic kidney disease was diagnosed in patients with increased albuminuria and at least 10-year duration of diabetes or evidence of diabetic retinopathy. The skin biopsy was performed on distal part of lower leg, using a sterile, disposable 3 mm biopsy punch with plunger (Disposable Biopsy Punches, Integra™ Miltex®). In the immunohistochemical analyses, we used: anti-CD133, anti-CD34, anti-CD31, and anti-von Willebrand factor (vWF) autoantibodies. Microvessel density measurement in all specimens was performed using “hot spots technique”. Slides were scanned using the MiraxMidi scanner (Carl Zeiss) and were viewed using CaseViewer (3DHISTECH Ltd. Budapest, Hungary). Data were analyzed using Statistica v. 13 software. Results. In the study group 21 patients with diagnosis DKD+, as compared to 127 subjects withaout DKD–, had longer duration of diabetes [30 (IQR: 21–36) vs. 21 (16–28) years, p = 0.002], higher prevalence of hypertension [14 (67%) vs. 37 (29%), p = 0.002], lower estimated glomerular filtration rate (eGFR) [66 (55–88) vs. 94 (83–106) mL/min/1.73 m2, p < 0.001]. Median MVD compared between groups with and without DKD, was similar for CD34+ vessels/1 mm2 [123 (100–170) vs. 121 (100–170), p = 0.775], CD133+ vessels/1 mm2 [79 (50–100) vs. 79 (63–93), p = 0.823], and for CD31+ vessels/ 1 mm2 [29 (21–46) vs. 38 (17–58), p = 0.454]. Median MVD vWF+ vessels/1 mm2 was lower in the group with than without DKD: 42 (25–54) vs. 54 (43–71), p = 0.009. The values given above were calculated for both layers of the dermis (papillary and reticular dermis). In multivariate logistic regression analysis presence of diabetic kidney disease was associated with lower median vWF+ MVD [odds ratio: 0.97 (95% confidence interval: 0.95–0.99), p = 0.017], with adjustment for age, gender, eGFR value, diabetes duration and presence of hypertension. MVD did not differ significantly between chronic kidney disease stages. Conclusion. In patients with type 1 diabetes and diabetic kidney disease the disturbances in the angiogenesis and vascular maturation are present. The number of mature blood vessels (vWF+) in the skin is reduced. Disturbances in the angiogenesis occur at early stages of diabetic kidney disease.
Get Citation

Keywords

type 1 diabetes; diabetes complications; diabetic kidney disease; microcirculation; microvessel density (MVD); von Willebrand factor (vWF)

About this article
Title

Disturbances in angiogenesis and vascular maturation in the skin are associated with diabetic kidney disease in type 1 diabetes

Journal

Clinical Diabetology

Issue

Vol 8, No 5 (2019)

Pages

231-237

Published online

2019-08-26

DOI

10.5603/DK.2019.0019

Bibliographic record

Clinical Diabetology 2019;8(5):231-237.

Keywords

type 1 diabetes
diabetes complications
diabetic kidney disease
microcirculation
microvessel density (MVD)
von Willebrand factor (vWF)

Authors

Anna Adamska
Stanisław Piłaciński
Dorota Zozulińska-Ziółkiewicz
Agnieszka Gandecka
Agata Grzelka
Aneta Konwerska
Agnieszka Malińska
Michał Nowicki
Aleksandra Araszkiewicz

References (28)
  1. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis. 2007; 49(2 Suppl 2): S12–154.
  2. Harjutsalo V, Groop PH. Epidemiology and risk factors for diabetic kidney disease. Adv Chronic Kidney Dis. 2014; 21(3): 260–266.
  3. Macisaac RJ, Jerums G. Diabetic kidney disease with and without albuminuria. Curr Opin Nephrol Hypertens. 2011; 20(3): 246–257.
  4. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clin Diab. 2008; 26(2): 77–82.
  5. Sabatier F, Camoin-Jau L, Anfosso F, et al. Circulating endothelial cells, microparticles and progenitors: key players towards the definition of vascular competence. J Cell Mol Med. 2009; 13(3): 454–471.
  6. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997; 275(5302): 964–967.
  7. Peichev M, Naiyer AJ, Pereira D, et al. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood. 2000; 95(3): 952–958.
  8. Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem. 1998; 67: 395–424.
  9. Sandeman DD, Shore AC, Tooke JE. Relation of skin capillary pressure in patients with insulin-dependent diabetes mellitus to complications and metabolic control. N Engl J Med. 1992; 327(11): 760–764.
  10. Khan F, Elhadd TA, Greene SA, et al. Impaired skin microvascular function in children, adolescents, and young adults with type 1 diabetes. Diabetes Care. 2000; 23(2): 215–220.
  11. Østerby R, Hartmann A, Bangstad HJ. Structural changes in renal arterioles in type I diabetic patients. Diabetologia. 2002; 45(4): 542–549.
  12. Nakagawa T, Sato W, Kosugi T, et al. Abnormal angiogenesis in diabetic nephropathy. Diabetes. 2009; 58(7): 1471–1478.
  13. Joles JA, Braam B, Verhaar MC. ACE inhibition and glomerular repair: restructuring or regeneration? Kidney Int. 2006; 69(7): 1105–1107.
  14. Nakagawa T. Uncoupling of the VEGF-endothelial nitric oxide axis in diabetic nephropathy: an explanation for the paradoxical effects of VEGF in renal disease. Am J Physiol Renal Physiol. 2007; 292(6): F1665–F1672.
  15. Kim BS, Goligorsky MS. Role of VEGF in kidney development, microvascular maintenance and pathophysiology of renal disease. Korean J Intern Med. 2003; 18(2): 65–75.
  16. Adamska A, Pilacinski S, Zozulinska-Ziolkiewicz D, et al. An increased skin microvessel density is associated with neurovascular complications in type 1 diabetes mellitus. Diab Vasc Dis Res. 2019 [Epub ahead of print]: 1479164119850831.
  17. Masum MdA, Ichii O, Elewa YH, et al. Local CD34-positive capillaries decrease in mouse models of kidney disease associating with the severity of glomerular and tubulointerstitial lesions. BMC Nephrol. 2017; 18(1): 280.
  18. Aggarwal S, Grange C, Iampietro C, et al. Human CD133 renal progenitor cells induce erythropoietin production and limit fibrosis after acute tubular injury. Sci Rep. 2016; 6: 37270.
  19. Adamska A, Araszkiewicz A, Pilacinski S, et al. Dermal microvessel density and maturity is closely associated with atherogenic dyslipidemia and accumulation of advanced glycation end products in adult patients with type 1 diabetes. Microvasc Res. 2019; 121: 46–51.
  20. Piera-Velazquez S, Jimenez SA. Endothelial to mesenchymal transition: role in physiology and in the pathogenesis of human diseases. Physiol Rev. 2019; 99(2): 1281–1324.
  21. Peng H, Li Y, Wang C, et al. ROCK1 induces endothelial-to-mesenchymal transition in glomeruli to aggravate albuminuria in diabetic nephropathy. Sci Rep. 2016; 6: 20304.
  22. Liu F, Zhang S, Xu R, et al. Melatonin attenuates endothelial-to-mesenchymal transition of glomerular endothelial cells via regulating miR-497/ROCK in diabetic nephropathy. Kidney Blood Press Res. 2018; 43(5): 1425–1436.
  23. van Schie MC, van Loon JE, de Maat MPM, et al. Genetic determinants of von Willebrand factor levels and activity in relation to the risk of cardiovascular disease: a review. J Thromb Haemost. 2011; 9(5): 899–908.
  24. Smith NL, Rice KM, Bovill EG, et al. Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis. Blood. 2011; 117(22): 6007–6011.
  25. Lenting PJ, Casari C, Christophe OD, et al. von Willebrand factor: the old, the new and the unknown. J Thromb Haemost. 2012; 10(12): 2428–2437.
  26. Edgell CJ, Haizlip JE, Bagnell CR, et al. Endothelium specific Weibel-Palade bodies in a continuous human cell line, EA.hy926. In Vitro Cell Dev Biol. 1990; 26(12): 1167–1172.
  27. Tsai WC, Wu HY, Peng YS, et al. Risk factors for development and progression of chronic kidney disease: a systematic review and exploratory meta-analysis. Medicine (Baltimore). 2016; 95(11): e3013.
  28. Fogo AB. Mechanisms of progression of chronic kidney disease. Pediatr Nephrol. 2007; 22(12): 2011–2022.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

 

Wydawcą serwisu jest  "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl