GIV/Girdin Links Vascular Endothelial Growth Factor Signaling to Akt Survival Signaling in Podocytes Independent of Nephrin

Abstract

Podocytes are critically involved in the maintenance of the glomerular filtration barrier and are key targets of injury in many glomerular diseases. Chronic injury leads to progressive loss of podocytes, glomerulosclerosis, and renal failure. Thus, it is essential to maintain podocyte survival and avoid apoptosis after acute glomerular injury. In normal glomeruli, podocyte survival is mediated via nephrin-dependent Akt signaling. In several glomerular diseases, nephrin expression decreases and podocyte survival correlates with increased vascular endothelial growth factor (VEGF) signaling. How VEGF signaling contributes to podocyte survival and prevents apoptosis remains unknown. We show here that Gα-interacting, vesicle-associated protein (GIV)/girdin mediates VEGF receptor 2 (VEGFR2) signaling and compensates for nephrin loss. In puromycin aminonucleoside nephrosis (PAN), GIV expression increased, GIV was phosphorylated by VEGFR2, and p-GIV bound and activated Gαi3 and enhanced downstream Akt2, mammalian target of rapamycin complex 1 (mTORC1), and mammalian target of rapamycin complex-2 (mTORC2) signaling. In GIV-depleted podocytes, VEGF-induced Akt activation was abolished, apoptosis was triggered, and cell migration was impaired. These effects were reversed by introducing GIV but not a GIV mutant that cannot activate Gαi3. Our data indicate that after PAN injury, VEGF promotes podocyte survival by triggering assembly of an activated VEGFR2/GIV/Gαi3 signaling complex and enhancing downstream PI3K/Akt survival signaling. Because of its important role in promoting podocyte survival, GIV may represent a novel target for therapeutic intervention in the nephrotic syndrome and other proteinuric diseases.

Therapeutic effects of cell-permeant peptides that activate G proteins downstream of growth factors

“…First, it firms up an emerging hypothesis which challenges the long-held tenet that heterotrimeric G proteins are activated exclusively by GPCRs. Our recent work has revealed that RTKs can indeed interact with and activate Gαi (30) during a variety of pathophysiologic processes (7,14,21) using the C terminus of GIV as a platform for such RTK-G protein cross-talk (25). The findings described here using TAT-GIV-CT peptides represent a significant advancement in our ability to access, interrogate and manipulate that platform, and thereby, modulate the cross-talk it facilitates.…”

“…It is because cells can alter (increase or decrease) the levels of GIV mRNA/protein or selectively modulate GIV's GEF activity to modulate growth factor signaling pathways across a range of intensities (16), we likened GIV to a cellular "rheostat" for signal transduction (17). Consistent with its ability to integrate signals downstream of multiple receptors, GIV modulates growth factor signaling during diverse biological processes (17), e.g., cell migration, chemotaxis (13), invasion (18), development (19), self-renewal (20), apoptosis (14,21), and autophagy (12). Increasing evidence also supports the clinical significance of GIV-dependent signaling during diverse disease processes (17), e.g., pathologic angiogenesis (11), liver fibrosis (14), nephrotic syndrome (21), vascular repair (22), and tumor metastasis (23).…”

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

“…Mitochondrial function [65], β-integrin [66,67] VEGF-R blocker Positive (diabetes) [86,87], negative (other glomerular disease) [80,81,88,89] Apoptosis, podocyte effacement, nephrin [79] PPARγ, peroxisome proliferator-activated receptor gamma; RAAS, renin-angiotensin-aldosterone system; ACE, angiotensin-converting enzyme; AT1-R, angiotensin II type 1 receptor; HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-CoA lyase reductase; VEGF-R, vascular endothelial growth factor receptors; SMPDL-3b, sphingomyelin phosphodiesterase, acid-like 3B…”

“…Podocyte-specific heterozygous and homozygous deletions of VEGF results in proteinuria and endotheliosis in mice [78]. VEGF also has direct beneficial effects on podocyte survival independent of nephrin expression [79]. An endogenous condition when VEGF-A levels are reduced is preeclampsia.…”

Vascular Endothelial Growth Factor (VEGF) and Its Controversies about Nephrotic Syndrome and Diabetic Nephropathy: A Systematic Review

“…Circulating permeability factors also might be effective, because such factors seems apoptosis inducer for podocytes-cells that play the key physical role in glomerular filtration barrier [2]. Such factors are mainly synthesized and secreted by T cells existing in blood and regional capillaries [3,4].…”