Angiotensin II receptor blocker attenuates overexpression of vascular endothelial growth factor in diabetic podocytes

Abstract

Abbreviations: RT-PCR, reverse transcription-polymerase chain reaction; VEGF, vascular endothelial growth factor A bstract VEGF expressed in glomerular podocytes, is known to increase vascular perm eability to m acrom olecules. Angiotensin II can stim ulate the release of VEG F, and the protective effects of angiotensin II antagonist against diabetic glom erular injury suggest that the angiotensin II-induced VEG F is an im portant pathogenetic m echanism in the developm ent of proteinuria during diabetic nephropathy although this m echanism is not fully understood. In this study, the changes of VEG F expression was examined in the experimental diabetic nephropathy to determine whether these changes were modified by renoprotective intervention by blockers of angiotensin II receptors. The streptozotocininduced diabetic rats w ere treated w ith L-158,809, a blocker of angiotensin II receptors, for 12 weeks. Age-m atched rats w ith L-158,809 served as controls. R T-PC R and im m unohistochem istry w ere used to assess and quantify gene and protein expression of VEG F. A progressive increase in urinary protein excretion w as observed in diabetic rats. G lom erular VEG F expression w as significantly higher in diabetic rats than in the control groups, w ith a significant reduction in glom erular VEG F expression and proteinuria in L-158,809-treated diabetic rats. VEG F m RNA w as also significantly higher in diabetic kidneys than in the control groups, w ith a significant reduction in VEG F m RNA in L-158,809-treated diabetic kidneys. These results dem onstrates that VEG F expression is significantly increased in diabetic podocytes, and angiotensin II receptor antagonist attenuated these changes in VEG F expression and prevented the developm ent of proteinuria in vivo. Attenuation of increased VEGF expression in podocytes could contribute to the renoprotective effects of angiotensin II receptor antagonists in diabetic nephropathy.

Systemic and local effects of angiotensin II blockade in experimental diabetic nephropathy

“…It has been recently demonstrated that VEGF expression is upregulated in the kidney, mainly in the podocytes, of streptozotocin diabetic rat. 7,16,18 The podocytes intervene in the filtration barrier function and it has been suggested that enhanced VEGF in podocytes is mediating the increase in albumin permeability in diabetes. 7,16,36 This growth factor is down-regulated in the podocytes of diabetic rats chronically treated with an Ang II receptor antagonist.…”

“…7,16,18 The podocytes intervene in the filtration barrier function and it has been suggested that enhanced VEGF in podocytes is mediating the increase in albumin permeability in diabetes. 7,16,36 This growth factor is down-regulated in the podocytes of diabetic rats chronically treated with an Ang II receptor antagonist. 7 Moreover, Liu et al demonstrated that the increased expression of VEGF in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria.…”

“…7,16,36 This growth factor is down-regulated in the podocytes of diabetic rats chronically treated with an Ang II receptor antagonist. 7 Moreover, Liu et al demonstrated that the increased expression of VEGF in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria. 37 In accordance with all these data, we found that the treatment with Ang II receptor antagonist reduced the diabetes associated VEGF increase in glomeruli and proteinuria.…”

“…5,6 One possible explanation might be related to the growth effects exerted by angiotensin II (Ang II) on kidney cell, exerted through its angiotensin type (AT 1 ) receptor. 6 Some of the Ang II trophic effects in different cell types have been linked to the induction of the expression of growth factors such as vascular endothelial growth factor (VEGF) 7,8 or transforming growth factor-beta 1 (TGF-β 1 ). 9,10 TGF-β 1 has been extensively studied as a major mediator of the hypertrophic and prosclerotic changes in diabetic kidney disease.…”

“…Recent studies have related them to the existence of proteinuria in this disease. 7,[15][16][17][18] However, the roles of the local renin-angiotensin-system (RAS) and the growth factors mentioned above in the alterations of glomerular structure and function, and the eventual linkages between them in the glomerular compartment have not been characterised.…”