Acute Podocyte Vascular Endothelial Growth Factor (VEGF-A) Knockdown Disrupts alphaVbeta3 Integrin Signaling in the Glomerulus

Veron, de lma; Villegas, G.; Aggarwal, Pardeep K.; Bertuccio, Claudia A.; Jiménez, Juan Jiménez; Velázquez, Heino; Reidy, Kimberly; Abrahamson, Dale R.; Moeckel, Gilbert; Kashgarian, Michael; Tufró, Alda

doi:10.1371/journal.pone.0040589

Cited by 66 publications

(79 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…While mesangial cells are well known to produce fibronectin by various stimuli (53,54), recent studies showed that podocytes can also produce fibronectin, transforming growth factor-␤, angiotensin II, and high glucose upregulated fibronectin in cultured podocytes (25,34,39,55). Upregulation of the extracellular matrixes was also observed without clear evidence of podocytopenia in adriamycin nephropathy (19) or in a model of diabetic nephropathy (12), and fibronectin staining overlapped, at least partially, with nephrin in the mouse kidney consistent with fibronectin production by podocytes in addition to mesangial cells (70). Furthermore, some investigators propose that podocytes may undergo epithelialmesenchymal transition when the injury is progressive to escape from apoptotic cell death and that the associated phenotypic changes may contribute to impaired permselectivity (42).…”

mentioning

confidence: 78%

Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes

Zhu

Aoudjit

et al. 2013

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Glomerulosclerosis is featured by accumulation of the extracellular matrixes in the glomerulus. We showed previously that activation of the small GTPase RhoA in podocytes induces heavy proteinuria and glomerulosclerosis in the mouse. In the current study, we investigated the mechanism by which RhoA stimulates the production of one of the extracellular matrixes, fibronectin, by podocytes, specifically testing the role of nuclear factor of activated T cells (NFAT). Expression of constitutively active RhoA in cultured podocytes activated the fibronectin promoter, upregulated fibronectin protein, and activated NFAT. Expression of constitutively active NFAT in podocytes also activated the fibronectin promoter and upregulated fibronectin protein. RhoA-induced NFAT activation and fibronectin upregulation were both dependent on the calcium/calmodulin pathway and Rho kinase. NFAT activation was also observed in vivo in the rat and mouse models of podocyte injury and proteinuria, and NFAT inhibition ameliorated fibronectin upregulation in the latter. RhoA activation induced a rise of intracellular calcium ion concentration ([Ca2+]i), which was at least in part dependent on the transient receptor potential canonical 6 (TRPC6) cation channel. The results indicate that RhoA activates NFAT by inducing a rise of [Ca2+]i in podocytes, which in turn contributes to fibronectin upregulation. This pathway may be responsible for the pathogenesis of certain glomerular diseases such as hypertension-mediated glomerulosclerosis.

show abstract

mentioning

confidence: 78%

Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes

Zhu

Aoudjit

et al. 2013

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…11 These properties of ELP-VEGF may have extended the time for VEGF to bind to its receptors widely distributed in vascular endothelial cells, glomerular cells, and podocytes, 32,39 and amplified autocrine/ paracrine actions of VEGF in the kidney, 40,41 as in turn may explain the superior efficacy over unconjugated VEGF therapy. However, a potential limitation of our study may be that the model may represent an early stage of RVD and that only one time-point was evaluated, since RVD in humans is a slowly progressive disease and intrinsic kidney damage develops over months and years.…”

Section: Discussionmentioning

confidence: 99%

Renal Therapeutic Angiogenesis Using a Bioengineered Polymer-Stabilized Vascular Endothelial Growth Factor Construct

Chade¹,

Tullos²,

Harvey³

et al. 2015

JASN

104

View full text Add to dashboard Cite

Renovascular disease (RVD) induces renal microvascular (MV) rarefaction that drives progressive kidney injury. In previous studies, we showed that renal vascular endothelial growth factor (VEGF) therapy attenuated MV damage, but did not resolve renal injury at practical clinical doses. To increase the bioavailability of VEGF, we developed a biopolymer-stabilized elastin-like polypeptide (ELP)-VEGF fusion protein and determined its in vivo potential for therapeutic renal angiogenesis in RVD using an established swine model of chronic RVD. We measured single-kidney blood flow (RBF) and GFR and established the degree of renal damage after 6 weeks of RVD. Pigs then received a single stenotic kidney infusion of ELP-VEGF (100 mg/kg), a matching concentration of unconjugated VEGF (18.65 mg/kg), ELP alone (100 mg/kg), or placebo. Analysis of organ distribution showed high renal binding of ELP-VEGF 4 hours after stenotic kidney infusion. Therapeutic efficacy was determined 4 weeks after infusion. ELP-VEGF therapy improved renal protein expression attenuated in RVD, restoring expression levels of VEGF, VEGF receptor Flk-1, and downstream angiogenic mediators, including phosphorylated Akt and angiopoietin-1 and -2. This effect was accompanied by restored MV density, attenuated fibrogenic activity, and improvements in RBF and GFR greater than those observed with placebo, ELP alone, or unconjugated VEGF. In summary, we demonstrated the feasibility of a novel therapy to curtail renal injury. Recovery of the stenotic kidney in RVD after ELP-VEGF therapy may be driven by restoration of renal angiogenic signaling and attenuated fibrogenic activity, which ameliorates MV rarefaction and improves renal function. 27: 174127: -175227: , 201627: . doi: 10.1681 Renal vascular disease (RVD), usually caused by renal artery stenosis, can lead to CKD and ESRD. RVD increases cardiovascular morbidity and mortality, hospitalization, shortens life expectancy, and is increasing at a sustained pace in the United States. 1 Moreover, renal function does not improve or even deteriorates in almost half of the patients with RVD despite treatment. Recent clinical studies suggest that patients undergoing current therapeutic strategies, which include drugs and renal angioplasty, do not show differences in outcomes that could demonstrate distinct benefits of one treatment over the other when compared side by side. 2,3 Moreover, renal function does not improve or even deteriorates in almost half of patients with RVD despite treatment, highlighting a pressing need for novel therapeutic strategies for the growing population of patients suffering from RVD. J Am Soc NephrolUsing a clinically relevant swine model of chronic RVD that mimics several of the pathologic features

show abstract

“…The role of podocyte VEGF-A in regulating α V β 3 integrin signaling in the mouse GBM has been shown in vivo [47]. α V β 3 integrin plays an important role in angiogenesis and in hypertension-induced vascular remodeling in the kidney.…”

Section: Podocyte-endothelial Cell Link and Vascular Endothelial Growmentioning

confidence: 99%

A Review of Podocyte Biology

Garg¹

2018

Am J Nephrol

223

169

View full text Add to dashboard Cite

Background: Podocyte biology is a developing science that promises to help improve understanding of the mechanistic nature of multiple diseases associated with proteinuria. Proteinuria in nephrotic syndrome has been linked to mechanistic dysfunctions in the renal glomerulus involving the function of podocyte epithelial cells, including podocyte foot process effacement. Summary: Developments in imaging technology are improving knowledge of the detailed structure of the human renal glomerulus and cortex. Podocyte foot processes attach themselves to the glomerular capillaries at the glomerular basement membrane (GBM) forming intercellular junctions that form slit diaphragm filtration barriers that help maintain normal renal function. Damage in this area has been implicated in glomerular disease. Injured podocytes undergo effacement whereby they lose their structure and spread out, leading to a reduction in filtration barrier function. Effacement is typically associated with the presence of proteinuria in focal segmental glomerulosclerosis, minimal change disease, and diabetes. It is thought to be due to a breakdown in the actin cytoskeleton of the foot processes, complex contractile apparatuses that allow podocytes to dynamically reorganize according to changes in filtration requirements. The process of podocyte depletion correlates with the development of glomerular sclerosis and chronic kidney disease. Focal adhesion complexes that interact with the underlying GBM bind the podocytes within the glomerular structure and prevent their detachment. Key Messages: Knowledge of glomerular podocyte biology is helping to advance our understanding of the science and mechanics of the glomerular filtering process, opening the way to a variety of new potential applications for clinical targeting.

show abstract

Acute Podocyte Vascular Endothelial Growth Factor (VEGF-A) Knockdown Disrupts alphaVbeta3 Integrin Signaling in the Glomerulus

Cited by 66 publications

References 50 publications

Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes

Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes

Renal Therapeutic Angiogenesis Using a Bioengineered Polymer-Stabilized Vascular Endothelial Growth Factor Construct

A Review of Podocyte Biology

Contact Info

Product

Resources

About