Possible Role of VEGF in the Progression of Kidney Disease in Streptozotocin (STZ)-induced Diabetic Rats: Effects of an ACE Inhibitor and an Angiotensin II Receptor Antagonist

Kakizawa, Hiroko; Itoh, Yoko; Imamura, Shigeo; Matsumoto, T.; Ishiwata, Yasuo; Ōno, Yoshiaki; Yamamoto, Kohji; Kato, Takeshi; Hayakawa, Naohiro; Oda, Naoki; Goto, Yoshie; Nagasaka, Akio; Senda, Toshihiko; Itoh, Misao

doi:10.1055/s-2004-825725

Cited by 18 publications

(16 citation statements)

References 31 publications

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“…Recent studies indicate that VEGF is actively involved in the pathogenesis of diabetic nephropathy (36,46,47). Results from our study do confirm those previous findings and support the theory that altered lipid accumulation is contributing to the development of diabetic nephropathy.…”

Section: Discussionsupporting

confidence: 83%

Regulation of Renal Lipid Metabolism, Lipid Accumulation, and Glomerulosclerosis in FVBdb/db Mice With Type 2 Diabetes

et al. 2005

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Diabetic kidney disease has been associated with the presence of lipid deposits, but the mechanisms for the lipid accumulation have not been fully determined. In the present study, we found that db/db mice on the FVB genetic background with loss-of-function mutation of the leptin receptor (FVB-Lepr db mice or FVB db/db ) develop severe diabetic nephropathy, including glomerulosclerosis, tubulointerstitial fibrosis, increased expression of type IV collagen and fibronectin, and proteinuria, which is associated with increased renal mRNA abundance of transforming growth factor-␤, plasminogen activator inhibitor-1, and vascular endothelial growth factor. Electron microscopy demonstrates increases in glomerular basement membrane thickness and foot process (podocyte) length. We found that there is a marked increase in neutral lipid deposits in glomeruli and tubules by oil red O staining and biochemical analysis for cholesterol and triglycerides. We also detected a significant increase in the renal expression of adipocyte differentiation-related protein (adipophilin), a marker of cytoplasmic lipid droplets. We examined the expression of sterol regulatory element-binding protein (SREBP)-1 and -2, transcriptional factors that play an important role in the regulation of fatty acid, triglyceride, and cholesterol synthesis. We found significant increases in SREBP-1 and -2 protein levels in nuclear extracts from the kidneys of FVB db/db mice, with increases in the mRNA abundance of acetyl-CoA carboxylase, fatty acid synthase, and 3-hydroxy-3-methylglutaryl-CoA reductase, which mediates the increase in renal triglyceride and cholesterol content. Our results indicate that in FVB db/db mice, renal triglyceride and cholesterol accumulation is mediated by increased activity of SREBP-1 and -2. Based on our previous results with transgenic mice overexpressing SREBP-1 in the kidney, we propose that increased expression of SREBPs plays an important role in causing renal lipid accumulation, glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria in mice with type 2 diabetes.

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Section: Discussionsupporting

confidence: 83%

Regulation of Renal Lipid Metabolism, Lipid Accumulation, and Glomerulosclerosis in FVBdb/db Mice With Type 2 Diabetes

et al. 2005

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“…antibody-treated vs. control db/db diabetic mice but commented that the urinary excretion of albumin factored for creatinine clearance was slightly lower in the anti-TGF-␤ antibody-treated group, which is consistent with results in the present study. Upregulation of renal VEGF and VEGFRs has been found in rodents with experimental diabetes, although an early increase in VEGFR-2 ϳ3 wk after induction of diabetes is followed by a decline (16,27,31,36), which may explain the unchanged renal VEGFR-2 protein levels in the present study, which analyzed renal cortex from db/db mice that, at 18 -19 wk of age, had been diabetic for ϳ14 wk. VEGF signaling has been implicated in the differential glomerular expression of collagen IV subchains (7,8,26), which encompass the ␣ 1 (IV) and ␣ 2 (IV) chains predominant in the mesangial matrix and the ␣ 3 (IV) and ␣ 5 (IV) chains in the glomerular basement membrane produced by endothelial cells and podocytes (39,40).…”

Section: Discussionmentioning

confidence: 91%

Inhibiting albumin glycation attenuates dysregulation of VEGFR-1 and collagen IV subchain production and the development of renal insufficiency

Cohen¹,

Lautenslager²,

Hud³

et al. 2007

American Journal of Physiology-Renal Physiology

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CW. Inhibiting albumin glycation attenuates dysregulation of VEGFR-1 and collagen IV subchain production and the development of renal insufficiency. Am J Physiol Renal Physiol 292: F789 -F795, 2007. First published October 3, 2006; doi:10.1152/ajprenal.00201.2006.-Glomerular cells in culture respond to albumin containing Amadori glucose adducts (the principal serum glycated protein), with activation of protein kinase C-␤1, increased expression of transforming growth factor (TGF)-␤1, the TGF-␤ type II signaling receptor, and the extracellular matrix proteins ␣1(IV) collagen and fibronectin and with decreased production of the podocyte protein nephrin. Decreasing the burden of glycated albumin in diabetic db/db mice significantly reduces glomerular overexpression of TGF-␤1 mRNA, restores glomerular nephrin immunofluorescence, and lessens proteinuria, mesangial expansion, renal extracellular matrix protein production, and increased glomerular vascular endothelial growth factor (VEGF) immunostaining. In the present study, db/db mice were treated with a small molecule, designated 23CPPA, that inhibits the nonenzymatic condensation of glucose with the albumin protein to evaluate whether increased glycated albumin influences the production of VEGF receptors (VEGFRs) and type IV collagen subchains and ameliorates the development of renal insufficiency. Renal levels of VEGF and VEGFR-1 proteins and serum creatinine concentrations were significantly higher and renal levels of ␣3(IV) collagen and nephrin proteins and endogenous creatinine clearance values were significantly lower in control diabetic than in age-matched nondiabetic (db/m) mice. These changes were significantly attenuated in db/db littermate mice treated from 9 to 18 wk of age with 23CPPA. The findings indicate that inhibiting excess nonenzymatic glycation of serum albumin improves renal molecular biology abnormalities and protects against the development of renal insufficiency in the db/db mouse. diabetes; glycated albumin GLOMERULAR CELLS IN CULTURE respond, in a euglycemic milieu, to albumin modified by Amadori glucose adducts with activation of protein kinase C-␤ 1 and extracellular signal-regulated kinase, upregulation of the transforming growth factor (TGF)-␤ system, increased production of extracellular matrix proteins, and reduced expression of the podocyte protein nephrin (4,6,12,13,15,19). The relevance of these observations to the pathogenesis of diabetic nephropathy in vivo is supported by results of animal studies, which have shown that treatment of diabetic db/db mice with a small molecule that inhibits the nonenzymatic glycation of serum albumin decreases the glomerular mRNA expression of TGF-␤1, prevents depletion of glomerular nephrin (quantified by immunofluorescence), ameliorates mesangial expansion and mRNA overexpression of the extracellular matrix proteins ␣ 1 (IV) collagen and fibronectin, and lessens the urinary excretion of albumin and type IV collagen (measured as mg/24 h and ng/24 h, respectively) (9, 14). This treatment has also b...

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“…In cultured podocytes, VEGF expression can be stimulated by high glucose concentrations (91), by TGF-␤1 (91,92), and by ANG II acting via AT 1 and AT 2 receptors (93,94). The gene expression of VEGF is also stimulated by a transcription factor called hypoxia-inducible factor-1 (95).…”

Section: Role Of Vascular Endothelial Growth Factormentioning

confidence: 99%

From the Periphery of the Glomerular Capillary Wall Toward the Center of Disease

2005

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Possible Role of VEGF in the Progression of Kidney Disease in Streptozotocin (STZ)-induced Diabetic Rats: Effects of an ACE Inhibitor and an Angiotensin II Receptor Antagonist

Cited by 18 publications

References 31 publications

Regulation of Renal Lipid Metabolism, Lipid Accumulation, and Glomerulosclerosis in FVBdb/db Mice With Type 2 Diabetes

Regulation of Renal Lipid Metabolism, Lipid Accumulation, and Glomerulosclerosis in FVBdb/db Mice With Type 2 Diabetes

Inhibiting albumin glycation attenuates dysregulation of VEGFR-1 and collagen IV subchain production and the development of renal insufficiency

From the Periphery of the Glomerular Capillary Wall Toward the Center of Disease

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