Journal Article

Long-term blockade of vascular endothelial growth factor receptor-2 aggravates the diabetic renal dysfunction associated with inactivation of the Akt/eNOS-NO axis

Hyung Wook Kim, Ji Hee Lim, Min Young Kim, Sungjin Chung, Seok Joon Shin, Hyun Wha Chung, Bum Soon Choi, Yong-Soo Kim, Yoon Sik Chang and Cheol Whee Park

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 26, issue 4, pages 1173-1188
Published in print April 2011 | ISSN: 0931-0509
Published online October 2010 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfq610
Long-term blockade of vascular endothelial growth factor receptor-2 aggravates the diabetic renal dysfunction associated with inactivation of the Akt/eNOS-NO axis

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Background. Diabetic nephropathy is characterized by abnormal angiogenesis, and this is driven by several factors, including hyperglycaemia and ischaemia. We investigated the role of vascular endothelial growth factor receptor-2 (VEGFR-2) blockade and its effects on diabetic nephropathy.

Methods. Male db/db and db/m mice received long-term treatment with dRK6, an arginine-rich anti-VEGF hexapeptide, for 12 weeks or short-term treatment for only the first 4 weeks, starting from 8 weeks of age.

Results. The urinary albuminuria and VEGF excretion varied according to the duration of diabetes, and the urinary VEGF levels were strongly correlated with the levels of albuminuria. Diabetes increased the VEGFR-2 expression in the kidneys. At the end of the 12-week study, compared with the db/db control mice, the db/db mice with long-term dRK6 treatment, which selectively inhibited VEGFR-2, had more albuminuria, related to weak nephrin signalling and advanced renal phenotypes, which were associated with hypoxia-oxidative stress, and an increased number of apoptotic endothelial cells. Interestingly, these changes were related to a decrease in phospho-Akt/eNOS-NO bioavailability. On the in vitro study, dRK6 increased the number of apoptotic human umbilical vein endothelial cells (HUVECs) in the high glucose media by blocking phospho-Akt/eNOS-NO signalling, and this was related to the increased oxidative stress. The short-term inhibition of VEGFR-2 neither improved the albuminuria nor the renal phenotype induced by diabetes.

Conclusions. Long-term selective blockade of VEGFR-2 by dRK6 had deleterious renal effects, and this was associated with downregulation of the Akt/eNOS-NO axis in db/db mice. Short-term VEGFR-2 blockade did not improve the renal phenotypes and the albuminuria. These findings suggest that VEGF-A-VEGFR-2 inhibition, regardless of how long it may be, does not ameliorate diabetic nephropathy in type 2 diabetes.

Keywords: Akt/protein kinase B; diabetic nephropathy; eNOS; nitric oxide; VEGF-A-VEGFR-2

Journal Article.  6861 words.  Illustrated.

Subjects: Nephrology

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