| 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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MedLine Citation:
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PMID: 20935017 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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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. |
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Authors:
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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; Cheol Whee Park |
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Publication Detail:
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Type: Journal Article Date: 2010-10-08 |
Journal Detail:
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Title: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Volume: 26 ISSN: 1460-2385 ISO Abbreviation: Nephrol. Dial. Transplant. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-04 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8706402 Medline TA: Nephrol Dial Transplant Country: England |
Other Details:
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Languages: eng Pagination: 1173-88 Citation Subset: IM |
Affiliation:
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Correspondence and offprint requests to: Cheol Whee Park; E-mail: cheolwhee@hanmail.net. |
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