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.
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.
Authors: Darren A Yuen; Bailey E Stead; Yanling Zhang; Kathryn E White; M Golam Kabir; Kerri Thai; Suzanne L Advani; Kim A Connelly; Tomoko Takano; Lei Zhu; Alison J Cox; Darren J Kelly; Ian W Gibson; Takamune Takahashi; Raymond C Harris; Andrew Advani Journal: J Am Soc Nephrol Date: 2012-09-20 Impact factor: 10.121
Authors: Sebastian Oltean; Yan Qiu; Joanne K Ferguson; Megan Stevens; Chris Neal; Amy Russell; Amit Kaura; Kenton P Arkill; Kirstie Harris; Clare Symonds; Katja Lacey; Lihini Wijeyaratne; Melissa Gammons; Emma Wylie; Richard P Hulse; Chloe Alsop; George Cope; Gopinath Damodaran; Kai B Betteridge; Raina Ramnath; Simon C Satchell; Rebecca R Foster; Kurt Ballmer-Hofer; Lucy F Donaldson; Jonathan Barratt; Hans J Baelde; Steven J Harper; David O Bates; Andrew H J Salmon Journal: J Am Soc Nephrol Date: 2014-12-26 Impact factor: 10.121
Authors: Andrew Advani; Kim A Connelly; Suzanne L Advani; Kerri Thai; Yuan Zhang; Darren J Kelly; Richard E Gilbert Journal: Biomed Res Int Date: 2013-08-22 Impact factor: 3.411
Authors: Seon Ha Baek; Hyunsuk Kim; Jeonghwan Lee; Dong Ki Kim; Kook-Hwan Oh; Yon Su Kim; Jin Suk Han; Tae Min Kim; Se-Hoon Lee; Kwon-Wook Joo Journal: Korean J Intern Med Date: 2014-01-02 Impact factor: 2.884