Insulin directly stimulates VEGF-A production in the glomerular podocyte

L.J. Hale, J. Hurcombe, A. Lay, B. Santamaría, A.M. Valverde, M.A. Saleem, P.W. Mathieson, G.I. Welsh, R.J. Coward

Research output: Contribution to journalArticlepeer-review

Abstract

Podocytes are critically important for maintaining the integrity of the glomerular filtration barrier and preventing albuminuria. Recently, it has become clear that to achieve this, they need to be insulin sensitive and produce an optimal amount of VEGF-A. In other tissues, insulin has been shown to regulate VEGF-A release, but this has not been previously examined in the podocyte. Using in vitro and in vivo approaches, in the present study, we now show that insulin regulates VEGF-A in the podocyte in both mice and humans via the insulin receptor (IR). Insulin directly increased VEGF-A mRNA levels and protein production in conditionally immortalized wild-type human and murine podocytes. Furthermore, when podocytes were rendered insulin resistant in vitro (using stable short hairpin RNA knockdown of the IR) or in vivo (using transgenic podocyte-specific IR knockout mice), podocyte VEGF-A production was impaired. Importantly, in vivo, this occurs before the development of any podocyte damage due to podocyte insulin resistance. Modulation of VEGF-A by insulin in the podocyte may be another important factor in the development of glomerular disease associated with conditions in which insulin signaling to the podocyte is deranged.

the podocyte is the major source of VEGF-A in the glomerulus of the kidney (21). It is critical for normal kidney function both during development (10) and in maturity (9). Podocyte-derived VEGF-A is able to signal to all three cell types in the glomerulus (the glomerular endothelial cell, the mesangial cell, and back to itself) (8). Furthermore, it is now clear that there is an optimal dosage at which this molecule is beneficial for glomerular function and that both low and high levels of VEGF-A can be detrimental (10, 28). Therefore, understanding how this molecule is controlled is desirable.

Our group and others have demonstrated that the podocyte is an insulin-responsive cell in humans (5) and mice (30, 33). Furthermore, loss of podocyte insulin responsiveness in the intact perfused glomerulus results in glomerular pathology with a number of features characteristic of diabetic nephropathy (DN), including increased matrix production, glomerulosclerosis, thickening of the glomerular basement membrane, and, with time, podocyte apoptosis (33). Importantly, all of this occurs in a normoglycemic environment, demonstrating that these features are not due to glucose toxicity.

Closely related to insulin are the insulin-like growth factors (IGFs), IGF-I and IGF-II. They are structurally similar to insulin and signal predominantly through the related IGF-I receptor (IGF-IR). It is also possible for insulin to signal through the IGF-IR and IGFs to signal via the IR, although with much less affinity for the other families' receptor (20).

Recently, we (13) have dissected out the role of IGF signaling in the podocyte. We have shown that IGF-I and IGF-II signal predominantly through the IGF-IR and that these pathways are critically important for podocyte survival. When the receptor is stably knocked down in these cells, there is significant cell death as they mature (13).

In other cells of the body, insulin is able to directly activate cellular VEGF-A production, including in white adipose tissue (19), cardiomyocytes (3), and retinal pigment epithelial cells in the eye (18, 22). In the present study, we now show that insulin (but, interestingly, not IGFs) stimulates VEGF-A production in the podocyte in vitro and in vivo predominantly via the IR.
Original languageUndefined
JournalAmerican Journal of Physiology - Renal Physiology
DOIs
Publication statusPublished - 15 Jul 2013

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