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VEGFC reduces glomerular albumin permeability and protects against alterations in VEGF receptor expression in diabetic nephropathy

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VEGFC reduces glomerular albumin permeability and protects against alterations in VEGF receptor expression in diabetic nephropathy. / Onions, Karen L.; Gamez, Monica; Buckner, Nicola R.; Baker, Siân L.; Betteridge, Kai B.; Desideri, Sara; Dallyn, Benjamin P.; Ramnath, Raina D.; Neal, Chris R; Farmer, Louise K.; Mathieson, Peter W.; Gnudi, Luigi; Alitalo, Kari; Bates, David O.; Salmon, Andrew H.J.; Welsh, Gavin I.; Satchell, Simon C.; Foster, Rebecca R.

In: Diabetes, Vol. 68, No. 1, 01.2019, p. 172-187.

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@article{8239e122cd304702a4754f1df2e6443d,
title = "VEGFC reduces glomerular albumin permeability and protects against alterations in VEGF receptor expression in diabetic nephropathy",
abstract = "Elevated levels of vascular endothelial growth factor (VEGF) A are thought to cause glomerular endothelial cell (GEnC) dysfunction and albuminuria in diabetic nephropathy. We hypothesized that VEGFC could counteract these effects of VEGFA to protect the glomerular filtration barrier and reduce albuminuria. Isolated glomeruli were stimulated ex vivo with VEGFC, which reduced VEGFA- and type 2 diabetes–induced glomerular albumin solute permeability (Ps’alb). VEGFC had no detrimental effect on glomerular function in vivo when overexpression was induced locally in podocytes (podVEGFC) in otherwise healthy mice. Further, these mice had reduced glomerular VEGFA mRNA expression, yet increased glomerular VEGF receptor heterodimerization, indicating differential signaling by VEGFC. In a model of type 1 diabetes, the induction of podVEGFC overexpression reduced the development of hypertrophy, albuminuria, loss of GEnC fenestrations and protected against altered VEGF receptor expression. In addition, VEGFC protected against raised Ps’alb by endothelial glycocalyx disruption in glomeruli. In summary, VEGFC reduced the development of diabetic nephropathy, prevented VEGF receptor alterations in the diabetic glomerulus, and promoted both glomerular protection and endothelial barrier function. These important findings highlight a novel pathway for future investigation in the treatment of diabetic nephropathy.",
author = "Onions, {Karen L.} and Monica Gamez and Buckner, {Nicola R.} and Baker, {Si{\^a}n L.} and Betteridge, {Kai B.} and Sara Desideri and Dallyn, {Benjamin P.} and Ramnath, {Raina D.} and Neal, {Chris R} and Farmer, {Louise K.} and Mathieson, {Peter W.} and Luigi Gnudi and Kari Alitalo and Bates, {David O.} and Salmon, {Andrew H.J.} and Welsh, {Gavin I.} and Satchell, {Simon C.} and Foster, {Rebecca R.}",
year = "2019",
month = "1",
doi = "10.2337/db18-0045",
language = "English",
volume = "68",
pages = "172--187",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "1",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - VEGFC reduces glomerular albumin permeability and protects against alterations in VEGF receptor expression in diabetic nephropathy

AU - Onions, Karen L.

AU - Gamez, Monica

AU - Buckner, Nicola R.

AU - Baker, Siân L.

AU - Betteridge, Kai B.

AU - Desideri, Sara

AU - Dallyn, Benjamin P.

AU - Ramnath, Raina D.

AU - Neal, Chris R

AU - Farmer, Louise K.

AU - Mathieson, Peter W.

AU - Gnudi, Luigi

AU - Alitalo, Kari

AU - Bates, David O.

AU - Salmon, Andrew H.J.

AU - Welsh, Gavin I.

AU - Satchell, Simon C.

AU - Foster, Rebecca R.

PY - 2019/1

Y1 - 2019/1

N2 - Elevated levels of vascular endothelial growth factor (VEGF) A are thought to cause glomerular endothelial cell (GEnC) dysfunction and albuminuria in diabetic nephropathy. We hypothesized that VEGFC could counteract these effects of VEGFA to protect the glomerular filtration barrier and reduce albuminuria. Isolated glomeruli were stimulated ex vivo with VEGFC, which reduced VEGFA- and type 2 diabetes–induced glomerular albumin solute permeability (Ps’alb). VEGFC had no detrimental effect on glomerular function in vivo when overexpression was induced locally in podocytes (podVEGFC) in otherwise healthy mice. Further, these mice had reduced glomerular VEGFA mRNA expression, yet increased glomerular VEGF receptor heterodimerization, indicating differential signaling by VEGFC. In a model of type 1 diabetes, the induction of podVEGFC overexpression reduced the development of hypertrophy, albuminuria, loss of GEnC fenestrations and protected against altered VEGF receptor expression. In addition, VEGFC protected against raised Ps’alb by endothelial glycocalyx disruption in glomeruli. In summary, VEGFC reduced the development of diabetic nephropathy, prevented VEGF receptor alterations in the diabetic glomerulus, and promoted both glomerular protection and endothelial barrier function. These important findings highlight a novel pathway for future investigation in the treatment of diabetic nephropathy.

AB - Elevated levels of vascular endothelial growth factor (VEGF) A are thought to cause glomerular endothelial cell (GEnC) dysfunction and albuminuria in diabetic nephropathy. We hypothesized that VEGFC could counteract these effects of VEGFA to protect the glomerular filtration barrier and reduce albuminuria. Isolated glomeruli were stimulated ex vivo with VEGFC, which reduced VEGFA- and type 2 diabetes–induced glomerular albumin solute permeability (Ps’alb). VEGFC had no detrimental effect on glomerular function in vivo when overexpression was induced locally in podocytes (podVEGFC) in otherwise healthy mice. Further, these mice had reduced glomerular VEGFA mRNA expression, yet increased glomerular VEGF receptor heterodimerization, indicating differential signaling by VEGFC. In a model of type 1 diabetes, the induction of podVEGFC overexpression reduced the development of hypertrophy, albuminuria, loss of GEnC fenestrations and protected against altered VEGF receptor expression. In addition, VEGFC protected against raised Ps’alb by endothelial glycocalyx disruption in glomeruli. In summary, VEGFC reduced the development of diabetic nephropathy, prevented VEGF receptor alterations in the diabetic glomerulus, and promoted both glomerular protection and endothelial barrier function. These important findings highlight a novel pathway for future investigation in the treatment of diabetic nephropathy.

UR - http://www.scopus.com/inward/record.url?scp=85058886923&partnerID=8YFLogxK

U2 - 10.2337/db18-0045

DO - 10.2337/db18-0045

M3 - Article

C2 - 30389746

AN - SCOPUS:85058886923

VL - 68

SP - 172

EP - 187

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 1

ER -