Vegfa Protects the Glomerular Microvasculature in Diabetes

Overview

Journal Diabetes

Specialty Endocrinology

Date 2012 Oct 25

PMID 23093658

Citations 78

Authors

Gavasker A Sivaskandarajah

Marie Jeansson

Yoshiro Maezawa

Vera Eremina

Hans J Baelde

Susan E Quaggin

Affiliations

Soon will be listed here.

Abstract

Vascular endothelial growth factor A (VEGFA) expression is increased in glomeruli in the context of diabetes. Here, we tested the hypothesis that this upregulation of VEGFA protects the glomerular microvasculature in diabetes and that therefore inhibition of VEGFA will accelerate nephropathy. To determine the role of glomerular Vegfa in the development and progression of diabetic nephropathy, we used an inducible Cre-loxP gene-targeting system that enabled genetic deletion of Vegfa selectively from glomerular podocytes of wild-type or diabetic mice. Type 1 diabetes was induced in mice using streptozotocin (STZ). We then assessed the extent of glomerular dysfunction by measuring proteinuria, glomerular pathology, and glomerular cell apoptosis. Vegfa expression increased in podocytes in the STZ model of diabetes. After 7 weeks of diabetes, diabetic mice lacking Vegfa in podocytes exhibited significantly greater proteinuria with profound glomerular scarring and increased apoptosis compared with control mice with diabetes or Vegfa deletion without diabetes. Reduced local production of glomerular Vegfa in a mouse model of type 1 diabetes promotes endothelial injury accelerating the progression of glomerular injury. These results suggest that upregulation of VEGFA in diabetic kidneys protects the microvasculature from injury and that reduction of VEGFA in diabetes may be harmful.

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References

Izzedine H, Brocheriou I, Deray G, Rixe O . Thrombotic microangiopathy and anti-VEGF agents. Nephrol Dial Transplant. 2006; 22(5):1481-2. DOI: 10.1093/ndt/gfl565. View

Qi Z, Fujita H, Jin J, Davis L, Wang Y, Fogo A . Characterization of susceptibility of inbred mouse strains to diabetic nephropathy. Diabetes. 2005; 54(9):2628-37. DOI: 10.2337/diabetes.54.9.2628. View

Veron D, Reidy K, Bertuccio C, Teichman J, Villegas G, Jimenez J . Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int. 2010; 77(11):989-99. DOI: 10.1038/ki.2010.64. View

Eremina V, Jefferson J, Kowalewska J, Hochster H, Haas M, Weisstuch J . VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008; 358(11):1129-36. PMC: 3030578. DOI: 10.1056/NEJMoa0707330. View

Schrijvers B, De Vriese A, Tilton R, Van de Voorde J, Denner L, Lameire N . Inhibition of vascular endothelial growth factor (VEGF) does not affect early renal changes in a rat model of lean type 2 diabetes. Horm Metab Res. 2005; 37(1):21-5. DOI: 10.1055/s-2005-861027. View

Dumont D, Gradwohl G, Fong G, Auerbach R, Breitman M . The endothelial-specific receptor tyrosine kinase, tek, is a member of a new subfamily of receptors. Oncogene. 1993; 8(5):1293-301. View

Najafian B, Mauer M . Progression of diabetic nephropathy in type 1 diabetic patients. Diabetes Res Clin Pract. 2008; 83(1):1-8. DOI: 10.1016/j.diabres.2008.08.024. View

Osterby R, ASPLUND J, Bangstad H, Nyberg G, Rudberg S, Viberti G . Neovascularization at the vascular pole region in diabetic glomerulopathy. Nephrol Dial Transplant. 1999; 14(2):348-52. DOI: 10.1093/ndt/14.2.348. View

Stokes M, Erazo M, DAgati V . Glomerular disease related to anti-VEGF therapy. Kidney Int. 2008; 74(11):1487-91. DOI: 10.1038/ki.2008.256. View

10.

Piscione T, Wu M, Quaggin S . Expression of Hairy/Enhancer of Split genes, Hes1 and Hes5, during murine nephron morphogenesis. Gene Expr Patterns. 2004; 4(6):707-11. DOI: 10.1016/j.modgep.2004.04.007. View

11.

Nathan D, Genuth S, Lachin J, Cleary P, Crofford O, Davis M . The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329(14):977-86. DOI: 10.1056/NEJM199309303291401. View

12.

Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P . Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004; 165(1):35-52. PMC: 1618540. DOI: 10.1016/S0002-9440(10)63273-7. View

13.

Hohenstein B, Hausknecht B, Boehmer K, Riess R, Brekken R, Hugo C . Local VEGF activity but not VEGF expression is tightly regulated during diabetic nephropathy in man. Kidney Int. 2006; 69(9):1654-61. DOI: 10.1038/sj.ki.5000294. View

14.

Root H, Mirsky S, Ditzel J . Proliferative retinopathy in diabetes mellitus; review of eight hundred forty-seven cases. J Am Med Assoc. 1959; 169(9):903-9. DOI: 10.1001/jama.1959.03000260001001. View

15.

Robert B, Zhao X, Abrahamson D . Coexpression of neuropilin-1, Flk1, and VEGF(164) in developing and mature mouse kidney glomeruli. Am J Physiol Renal Physiol. 2000; 279(2):F275-82. DOI: 10.1152/ajprenal.2000.279.2.F275. View

16.

Lip P, Chatterjee S, Caine G, Hope-Ross M, Gibson J, Blann A . Plasma vascular endothelial growth factor, angiopoietin-2, and soluble angiopoietin receptor tie-2 in diabetic retinopathy: effects of laser photocoagulation and angiotensin receptor blockade. Br J Ophthalmol. 2004; 88(12):1543-6. PMC: 1772428. DOI: 10.1136/bjo.2004.048587. View

17.

Eremina V, Cui S, Gerber H, Ferrara N, Haigh J, Nagy A . Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. J Am Soc Nephrol. 2006; 17(3):724-35. DOI: 10.1681/ASN.2005080810. View

18.

Sison K, Eremina V, Baelde H, Min W, Hirashima M, Fantus I . Glomerular structure and function require paracrine, not autocrine, VEGF-VEGFR-2 signaling. J Am Soc Nephrol. 2010; 21(10):1691-701. PMC: 3013545. DOI: 10.1681/ASN.2010030295. View

19.

Pinkse G, Bouwman W, Jiawan-Lalai R, Terpstra O, Bruijn J, de Heer E . Integrin signaling via RGD peptides and anti-beta1 antibodies confers resistance to apoptosis in islets of Langerhans. Diabetes. 2006; 55(2):312-7. DOI: 10.2337/diabetes.55.02.06.db04-0195. View

20.

. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998; 352(9131):837-53. View