Podocyte-Derived Vascular Endothelial Growth Factor Mediates the Stimulation of α3(IV) Collagen Production by Transforming Growth Factor-β1 in Mouse Podocytes

Chen, Sheldon; Kasama, Yuki; Lee, Joseph S.; Jim, Belinda; Marín, M. Luisa; Ziyadeh, Fuad N.

doi:10.2337/diabetes.53.11.2939

Cited by 100 publications

(92 citation statements)

References 51 publications

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“…Downregulation of TGF-␤1 and VEGF in uremic animals treated with R-568 and calcitriol, respectively, was associated with decreases in collagen IV deposition and GBM thickness. In cultured podocytes, collagen IV synthesis is increased when VEGF signaling is stimulated (5). The finding of more glomerular collagen IV deposition and GBM thickening in uremic animals is interpreted as a response to injury (11) that is obviously ameliorated by R-568 or calcitriol.…”

Section: Discussionmentioning

confidence: 85%

Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats

Piecha¹,

Kökény²,

Nakagawa³

et al. 2008

American Journal of Physiology-Renal Physiology

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Patients with renal insufficiency develop secondary hyperparathyroidism. Monotherapy with active vitamin D or calcimimetics ameliorates secondary hyperparathyroidism. We compared kidney damage in subtotally nephrectomized (SNX) rats treated with active vitamin D (calcitriol) or the calcimimetic R-568. Male Sprague-Dawley SNX and sham-operated (sham-op) rats were randomized into the following treatment groups: SNX ϩ R-568, SNX ϩ calcitriol, SNX ϩ vehicle, sham-op ϩ R-568, sham-op ϩ calcitriol, and sham-op ϩ vehicle. Albuminuria and blood pressure were monitored and kidneys were examined using morphometry, immunohistochemistry, quantitative RT-PCR, and in situ hybridization. Parathyroid hormone concentrations were lowered to the same extent by the two interventions, although phosphorus and the calcium-phosphorus product were reduced only by R-568 treatment. SNX rats developed marked albuminuria, which was significantly reduced in ad libitum-and pair-fed animals treated with R-568 and animals treated with calcitriol. Mean glomerular volume (6.05 Ϯ 1.46 vs. 2.70 Ϯ 0.91 mm 3 ), podocyte volume (831 Ϯ 127 vs. 397 Ϯ 67 m 3 ), the degree of foot process fusion (mean width of foot processes ϭ 958 Ϯ 364 vs. 272 Ϯ 35 nm), and glomerular basement membrane thickness (244 Ϯ 6 vs. 267 Ϯ 23 nm), as well as desmin staining, were significantly higher in vehicletreated SNX than sham-operated animals. These changes were ameliorated with R-568 and calcitriol. In SNX, as well as sham-operated, animals, expression of the calcium-sensing receptor (protein and mRNA) was upregulated by treatment with the calcimimetic, but not calcitriol. Calcitriol and R-568 were similarly effective in ameliorating kidney damage. secondary hyperparathyroidism; chronic renal failure; nephroprotection; calcimimetics; calcitriol SECONDARY HYPERPARATHYROIDISM (sHPT) is a common feature of chronic kidney disease. Parathyroid hormone (PTH) concentrations increase progressively with diminishing glomerular filtration rate, but it is unclear whether PTH per se modifies progression.Active metabolites of vitamin D are widely used to control sHPT. Moreover, beneficial effects of active vitamin D on progression of chronic kidney disease have been documented (13,19).A therapeutic alternative is the use of calcimimetics (R-568 and, in humans, cinacalcet HCl), allosteric activators of the calcium-sensing receptor (CaSR), which reduce PTH secretion and interfere with parathyroid hyperplasia (4,20,22). In addition, however, Ogata et al. (17) showed that short-term treatment with R-568 reduces albuminuria and attenuates glomerular and tubulointerstitial lesions in subtotally nephrectomized (SNX) rats.The present study was designed to compare the effect of the two interventions on albuminuria and morphological lesions of the kidney in the SNX rat. The readouts were morphology and ultrastructure of podocytes, glomerulosclerosis index (GSI), and tubulointerstitial damage index, as well as expression profile of TGF-␤1, endothelin-1 (ET-1), and VEGF using immunohistochemistry a...

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Section: Discussionmentioning

confidence: 85%

Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats

Piecha¹,

Kökény²,

Nakagawa³

et al. 2008

American Journal of Physiology-Renal Physiology

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“…For example, addition of exogenous vascular endothelial growth factor (VEGF) to immortalized mouse podocytes increases the production of collagen ␣3(IV), and this is reversed by treatment with the VEGF receptor inhibitor, SU5416. 30 Additionally, cultured mouse podocytes treated with angiotensin II similarly upregulate collagen ␣3(IV), and this was also shown to be mediated by mechanisms involving TGF-␤ and VEGF signaling. 31 Immortalized podocytes also synthesize more ␣5(IV) collagen when cultured on NC1 hexamers of collagen IV purified from normal canine GBM.…”

Section: Discussionmentioning

confidence: 99%

Cellular Origins of Type IV Collagen Networks in Developing Glomeruli

Abrahamson

Hudson²,

Stroganova³

et al. 2009

Journal of the American Society of Nephrology

183

148

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Laminin and type IV collagen composition of the glomerular basement membrane changes during glomerular development and maturation. Although it is known that both glomerular endothelial cells and podocytes produce different laminin isoforms at the appropriate stages of development, the cellular origins for the different type IV collagen heterotrimers that appear during development are unknown. Here, immunoelectron microscopy demonstrated that endothelial cells, mesangial cells, and podocytes of immature glomeruli synthesize collagen ␣1␣2␣1(IV). However, intracellular labeling revealed that podocytes, but not endothelial or mesangial cells, contain collagen ␣3␣4␣5(IV). To evaluate the origins of collagen IV further, we transplanted embryonic kidneys from Col4a3-null mutants (Alport mice) into kidneys of newborn, wildtype mice. Hybrid glomeruli within grafts containing numerous host-derived, wildtype endothelial cells never expressed collagen ␣3␣4␣5(IV). Finally, confocal microscopy of glomeruli from infant Alport mice that had been dually labeled with anti-collagen ␣5(IV) and the podocyte marker anti-GLEPP1 showed immunolabeling exclusively within podocytes. Together, these results indicate that collagen ␣3␣4␣5(IV) originates solely from podocytes; therefore, glomerular Alport disease is a genetic defect that manifests specifically within this cell type. Basement membranes are thin sheets of extracellular matrix that underlie epithelial cells, including the vascular endothelium, and surround all muscle cells, Schwann cells, and adipocytes. They are composed of polymers of laminin and type IV collagen, and also contain nidogen/entactin, and proteoglycans. During glomerulogenesis, a basement membrane beneath developing endothelial cells fuses with a separate basement membrane layer beneath differentiating podocytes, to produce the glomerular basement membrane (GBM) shared on opposing surfaces by both cell types. 1 Unlike most basement membranes in the body, the laminin and collagen IV composition of the GBM changes temporally as the glomerulus develops. 2 The earliest GBMs of comma-and S-shaped nephrons contain laminin ␣1␤1␥1 (laminin 111), whereas those at later developmental stages and in adulthood contain laminin ␣5␤2␥1 (laminin 521). 2,3 Previously, we showed by postfixation immunoelectron microscopy that both endothelial cells and podocytes synthesize laminin ␣1 and ␤1 initially, and both cells then undergo a laminin isoform switch and synthesize laminin ␣5 and ␤2 as glomeruli mature. 4 The mechanism and reason why laminin replacement occurs are unknown, but

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“…The mechanism by which VEGF induces podocyte hypertrophy BASIC RESEARCH www.jasn.org is unknown but may possibly be mediated in an autocrine manner because podocytes not only produce VEGF but also express VEGF receptors. 16,17 Although this hypothesis remains to be verified, podocytes may have the potential to bind to the VEGF that they secrete themselves. Consistent with the previous finding that VEGF can also stimulate podocytes to proliferate and increase their survival in vitro, 18 we found that hypertrophic podocytes in Tg rabbits were increased in number and had two or more nuclei, suggesting that VEGF may enhance podocyte growth in vivo.…”

Section: Vegf and Glomerular Hypertrophymentioning

confidence: 99%

Increased Expression of Vascular Endothelial Growth Factor in Kidney Leads to Progressive Impairment of Glomerular Functions

Liu

Morimoto

Kitajima

et al. 2007

Journal of the American Society of Nephrology

105

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Vascular endothelial growth factor (VEGF) is an important mediator in maintaining normal kidney functions. In addition, several lines of evidence suggest that upregulation of VEGF in glomeruli may be associated with or cause renal dysfunction such as diabetic nephropathy. For elucidation of the pathologic consequences of high levels of VEGF in glomeruli, transgenic (Tg) rabbits that express human VEGF 165 isoform in both kidney and liver under the control of the human ␣-1-antitrypsin promoter were generated and characterized. With the use of heterozygous Tg rabbits and their littermates aged 8 to 55 wk, renal functions and structures were investigated. Compared with control rabbits, Tg rabbits exhibited progressive proteinuria with increased GFR at the early stage and decreased GFR at the later stage. Histologic examinations revealed that Tg rabbit kidneys were characterized by considerable glomerular hypertrophy as a result of increased proliferation of both glomerular capillaries and mesangial cells accompanied by prominent podocyte hypertrophy. With increasing age starting from 20 wk, Tg rabbit kidneys showed prominent formation of microaneurysms and capillary proliferation at the vascular pole area. At a later stage (55 wk), many glomeruli showed sclerosis and tuft collapse with the formation of glomerular cysts on a background of tubular atrophy and interstitial fibrosis. This study provides the first evidence that increased expression of VEGF in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria, suggesting that VEGF exerts multiple effects on the glomerular pathophysiologic processes.

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Podocyte-Derived Vascular Endothelial Growth Factor Mediates the Stimulation of α3(IV) Collagen Production by Transforming Growth Factor-β1 in Mouse Podocytes

Cited by 100 publications

References 51 publications

Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats

Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats

Cellular Origins of Type IV Collagen Networks in Developing Glomeruli

Increased Expression of Vascular Endothelial Growth Factor in Kidney Leads to Progressive Impairment of Glomerular Functions

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