Kidney glomeruli ultrafilter blood to generate urine and they are dysfunctional in a variety of kidney diseases. There are two key vascular growth factor families implicated in glomerular biology and function, namely the vascular endothelial growth factors (VEGFs) and the angiopoietins (Angpt). We present examples showing not only how these molecules help generate and maintain healthy glomeruli but also how they drive disease when their expression is dysregulated. Finally, we review how manipulating VEGF and Angpt signalling may be used to treat glomerular disease.

THE KIDNEY GLOMERULUS IS AN EPITHELIAL–ENDOTHELIAL SIGNALLING SYSTEM

The mammalian kidney glomerulus constitutes the mechanism through which blood is ultrafiltered to generate urine, with the retention of circulating cells and macromolecules such as albumin. The adult glomerulus consists of specialized epithelial cells called podocytes, together with the endothelium, mesangium and glomerular basement membrane (GBM) [1]. Podocyte cells have branching extensions called foot processes which abut each other at slit diaphragms [2]. These specialized tight junctions constitute the major size-selective barrier in the glomerulus preventing macromolecular egress into Bowman's space and are composed of proteins such as nephrin and podocin, mutations in which lead to massive protein leakage [3,4]. The glomerular endothelium is highly fenestrated with a unique ultrastructure lacking fenestrae diaphragms [5] as well as having a specific molecular signature compared with other vascular beds [6], properties which help facilitate a high permeability to water and small solutes [7]. The luminal side of the glomerular capillaries is covered by a cell surface layer called the glycocalyx consisting of proteoglycans [7] which also contributes to the permeability barrier of the glomerulus [8] (Figure 1).

Anatomy of the glomerular filtration barrier

Figure 1
Anatomy of the glomerular filtration barrier

Electron microscopy images (A: scanning, B and C: transmission) of the glomerular capillary filtration barrier. Podocyte (POD), endothelial cells (EC), GBM, endothelial surface layer–glycocalyx (ESL) (pictures courtesy of Dr Kathryn E White, University of Newcastle, U.K.).

Figure 1
Anatomy of the glomerular filtration barrier

Electron microscopy images (A: scanning, B and C: transmission) of the glomerular capillary filtration barrier. Podocyte (POD), endothelial cells (EC), GBM, endothelial surface layer–glycocalyx (ESL) (pictures courtesy of Dr Kathryn E White, University of Newcastle, U.K.).

A complex local autocrine/paracrine network consisting of vascular growth factors and vasoactive peptides is in place between podocytes and glomerular endothelial cells which is critical in maintaining the structure and integrity of the kidney filtration barrier. In the present review, we will focus on the role of two key vascular growth factor families which have been implicated in glomerular biology and function, namely vascular endothelial growth factor-A (VEGF-A) and the angiopoietins (Angpt). We will describe examples of how specific balances/levels between VEGF-A and Angpt lead to normal development, maintenance of healthy glomeruli or drive early stages/progression of disease. We will also discuss studies describing manipulation of VEGF-A and Angpt signalling as a possible novel therapy for glomerular diseases.

VASCULAR ENDOTHELIAL GROWTH FACTOR-A SIGNALLING IN THE GLOMERULUS

VEGF-A is a major vascular permeability and angiogenic factor acting through the receptor tyrosine kinase receptors VEGFR-1 and VEGFR-2 [9]. Several different isoforms are generated by alternative splicing of exons 6 and 7 of the VEGF-A gene, but the most studied form to-date is VEGF-A165 (VEGF-A164 in mice). Additional isoforms are also generated with a unique C-terminal sequence due to exon 8 distal splice site selection which are termed VEGF-Axxxb and have anti-angiogenic properties [10].

In healthy adult murine and human kidneys, VEGF-A is constitutively expressed in podocytes [1113] whereas its receptors VEGFR-1 and VEGFR-2 are predominately localized on the glomerular endothelial cells [11,14]. It is proposed that podocyte VEGF-A binds to its receptors on the endothelium of the capillary lumen by diffusive flux, an event that occurs against the flow of glomerular filtration [15]. This retrograde flow of VEGF-A is facilitated by the sub-podocyte space, the area between the podocyte cell body and the glomerular filtration barrier [16], where the filtrate accumulates before gaining access to the Bowman's space via small areas directly connected to the urinary space. This structure confers a resistance so changing the pressure in the sub-podocyte space (possibly modulated by a finely regulated contraction of the podocytes) could favour the movement of growth factors against the net filtration flow allowing podocyte-secreted molecules such as VEGF-A to interact with the endothelial/mesangial glomerular cellular compartments [17,18] (Figure 2A). Tightly controlled local levels of VEGF-A are critical for maintaining glomerular structure and integrity and this is highlighted by experimental evidence showing dysregulation of VEGF-A in many disease situations (Table 1).

Table 1
Alterations in the VEGF-A family in glomerular disease

↑, increased; ↓, decreased

Disease/Animal modelVEGF-A family expressionReferences
Type 1 DN Early stages: ↑ Vegfa mRNA in podocytes and Vegfr2 in glomerular endothelial cells in rat DN; inducible podocyte overexpression of Vegfa in otherwise normal healthy adult mice results in glomerular abnormalities similar to those in DN; ↑ VEGF-A165b mRNA in patients. [22,31,67
 Late stages: ↓ glomerular VEGF-A mRNA and activity in diabetic patients [28,44
Anti-GBM glomerulonephritis ↓ podocyte VEGF-A associated with loss of glomerular capillaries [53
Thrombotic microangiopathy Vegfa ablation in adult mice results in pathology similar to that seen in patients with thrombotic microangiopathy; ↑ VEGF-A protein expression in regenerating areas of the kidney including the glomerulus [47,49
Pre-eclampsia ↑ circulating sFlt1 in patients; sFlt1 administration to rats/mice leads to pre-eclampsia like symptoms; heterozygous knockout mice hypomorphic for Vegfa develop preeclampsia symptoms [57,61,62,64
Disease/Animal modelVEGF-A family expressionReferences
Type 1 DN Early stages: ↑ Vegfa mRNA in podocytes and Vegfr2 in glomerular endothelial cells in rat DN; inducible podocyte overexpression of Vegfa in otherwise normal healthy adult mice results in glomerular abnormalities similar to those in DN; ↑ VEGF-A165b mRNA in patients. [22,31,67
 Late stages: ↓ glomerular VEGF-A mRNA and activity in diabetic patients [28,44
Anti-GBM glomerulonephritis ↓ podocyte VEGF-A associated with loss of glomerular capillaries [53
Thrombotic microangiopathy Vegfa ablation in adult mice results in pathology similar to that seen in patients with thrombotic microangiopathy; ↑ VEGF-A protein expression in regenerating areas of the kidney including the glomerulus [47,49
Pre-eclampsia ↑ circulating sFlt1 in patients; sFlt1 administration to rats/mice leads to pre-eclampsia like symptoms; heterozygous knockout mice hypomorphic for Vegfa develop preeclampsia symptoms [57,61,62,64

Role of VEGF-A in glomerular physiology and disease

Figure 2
Role of VEGF-A in glomerular physiology and disease

In health, VEGF-A is expressed in the kidney podocyte to maintain glomerular structure and function (A). During the early phases of diabetic glomerulopathy, VEGF-A levels are raised which are associated with podocyte foot process fusion, basement membrane thickening, mesangial expansion and endothelial cell proliferation leading to albuminuria (B). Experimental blockade of VEGF-A during early DN improves disease progression by ameliorating structural diabetes-mediated alterations (C). Experimental deletion of podocyte VEGF-A in otherwise normal adult mice leads to features of thrombotic microangiopathy with swollen endothelial cells and dense sub-endothelial deposits in capillary loops with the subsequent appearance of abnormal podocytes as the disease progresses (D).

Figure 2
Role of VEGF-A in glomerular physiology and disease

In health, VEGF-A is expressed in the kidney podocyte to maintain glomerular structure and function (A). During the early phases of diabetic glomerulopathy, VEGF-A levels are raised which are associated with podocyte foot process fusion, basement membrane thickening, mesangial expansion and endothelial cell proliferation leading to albuminuria (B). Experimental blockade of VEGF-A during early DN improves disease progression by ameliorating structural diabetes-mediated alterations (C). Experimental deletion of podocyte VEGF-A in otherwise normal adult mice leads to features of thrombotic microangiopathy with swollen endothelial cells and dense sub-endothelial deposits in capillary loops with the subsequent appearance of abnormal podocytes as the disease progresses (D).

VEGF-A may also affect non-endothelial cell types in the glomerulus with both murine and human mesangial cells shown to express VEGFR-2 in disease conditions [19,20]. There is currently conflicting data as to whether VEGF-A has autocrine effects on podocytes themselves with some reports in mice using immunogold techniques showing VEGFR-2 to be expressed on these cells [21,22]. In contrast, quantitative real-time PCR studies on podocytes isolated from mouse glomeruli by fluorescence-activated cell sorting using a nephrin antibody have been unable to detect any VEGFR-2 expression [23].

VEGFR-1 expression has also been detected in the basal aspect of podocyte foot processes adjacent to the silt diaphragm in mice by immunogold [24]. The same group also detected VEGFR1 mRNA in human immortalized podocytes [24], a finding confirmed in differentiating mouse cells [25]. In contrast, other studies were unable to detect VEGFR-1 by immunogold techniques in either murine podocyte cell bodies or foot processes [21].

GLOMERULAR VEGF-A IN DIABETIC NEPHROPATHY

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the developed world [26] and characterized by podocyte foot process fusion, basement membrane thickening and mesangial expansion leading to albuminuria [27]. Histological examination of kidneys during the early stages of DN has also shown glomerular capillary angiogenesis in samples obtained from both patients with type 2 diabetes [28] and animal models [29,30]. The formation of new blood vessels in early DN is associated with elevated levels of podocyte VEGF-A (Figure 2B). In a rat model of short term diabetes (insulin deficient), mRNA levels of Vegfa in podocytes and Vegfr2 in glomerular endothelial cells are increased 3 weeks after administration of streptozotocin [31]. Other studies have found that raised glomerular VEGF-A directly leads to features of DN. Inducible podocyte-mediated overexpression of Vegfa in otherwise healthy adult mice results in glomerular abnormalities similar to those present in DN including proteinuria, glomerulomegaly, GBM thickening, mesangial expansion and podocyte effacement [22]. The pathophysiological role of VEGF-A in DN is also highlighted by the observation that manipulating local endogenous levels of VEGF-A has profound effects on the progression of DN with both podocyte Vegfa165 overexpression and knockdown in mice administered low-dose streptozotocin accelerating the progression of diabetic glomerulopathy [32,33]. It is likely that different pathophysiological mechanisms are responsible for these findings with higher VEGF-A level increasing glomerular extracellular matrix deposition, disrupting the endothelial cell glycocalyx and increasing vascular permeability; whereas a fall in VEGF-A in DN promotes endothelial cell apoptosis [22,33,34].

Other studies inhibiting VEGF-A in experimental animal models of diabetes successfully ameliorated proteinuria and glomerular damage [3537]. Treatment with a monoclonal anti-VEGF-A antibody during the first 6 weeks of diabetes decreases hyperfiltration, albuminuria and glomerular hypertrophy in rats [35]. Administration for 8 weeks of SU5416, a tyrosine-kinase inhibitor blocking VEGF receptor phosphorylation in diabetic db/db mice prevents the development of albuminuria [37]. Furthermore, inducible podocyte overexpression of soluble VEGFR-1 (sFlt1), a potent VEGF-A inhibitor [38], in mice made diabetic by administration of streptozotocin [21] reduces albuminuria and glomerulopathy 10 weeks later presumably by blocking the molecular events mediated by diabetes-induced VEGF-A overexpression (Figure 2C).

One of the key downstream pathways by which VEGF-A inhibition may exert its protective effect in DN is through alterations in endothelial nitric oxide (NO) synthase (eNOS) signalling. VEGF-A stimulates endothelial NO release, which preserves the integrity of interendothelial junctions in capillaries and inhibits angiogenesis and vascular permeability in physiologic non-diabetic conditions [39,40]. However, in DN, a condition of reduced NO availability, VEGF-A engages an NO-independent pathway which is deleterious leading to the formation of abnormal and excessive numbers of blood vessels [41,42]. The importance of the relationship between VEGF-A and NO in DN is highlighted by a study in which blockade of VEGFR2 with a small molecular antagonist reduced albuminuria and hyperfiltration in diabetic mice administered streptozotocin; an effect eliminated in transgenic mice lacking eNOS [43].

The increase in glomerular VEGF-A during early DN is not sustained and as chronic kidney disease progresses endogenous VEGF-A levels fall. In laser-capture microdissection studies glomerular VEGF-A mRNA levels are reduced in severely injured glomeruli from diabetic patients compared with healthy controls [44]. Using specific antibodies which detect either VEGF-A expression or bioactivity, elevated VEGF-A expression is found in all glomeruli of early stage diabetic patients compared with healthy controls. However, the activity of VEGF-A is only enhanced in the endothelium of mildly injured glomeruli and significantly reduced in more severely damaged glomeruli [28].

VEGF-A DEFICIENCY AND GLOMERULAR DISEASE

The importance of tightly controlled levels of glomerular VEGF-A is highlighted by other studies showing reduced podocyte VEGF-A levels as a potential mechanism for the progression of glomerular thrombotic microangiopathy in haemolytic uremic syndrome (HUS); a disorder which usually affects the glomerular vasculature of young children under 5 years leading to acute renal insufficiency [4547]. Inducible cell-specific Vegfa ablation in podocytes of adult mice results in glomerular barrier disruption (Figure 2D), proteinuria and pathology similar to that seen in patients with thrombotic microangiopathy [47]. Interestingly, blockade of VEGF-A signalling by anti-VEGF-A antibodies or small molecule inhibitors for the treatment of neoplastic diseases patients leads to the development of proteinuria and thrombotic microangiopathy as a side effect, confirming that reduced podocyte VEGF-A could be deleterious for glomerular health [47,48].

It has been postulated that VEGF-A plays an important role in the repair response following kidney damage by thrombotic microangiopathy. In mice with thrombotic microangiopathy induced by renal artery perfusion of sheep anti-concanavalin A, VEGF-A protein levels are up-regulated in regenerating areas of the kidney, including the glomerulus [49]. Daily injection of recombinant VEGF-A in the same model prevents glomerular capillary rarefaction, reduces the number of collapsed glomeruli and improves renal function [50].

VEGF-A levels are down-regulated also in rapid progressive glomerulonephritis, a disorder which is characterized by haematuria, proteinuria, a fast decline in glomerular filtration rate and the presence of glomerular crescents [51]. In an animal model of progressive glomerulonephritis induced by injecting rats with an anti-rat GBM antibody, the glomerular endothelium initially undergoes an initial burst of endothelial proliferation followed by apoptosis of these cells as sclerosis progressed [52]. The loss of glomerular capillaries is associated with a reduction in podocyte VEGF-A expression as evaluated by immunohistochemistry [53]. Administration of recombinant VEGF-A in this model at a time-point when glomerular lesions have already formed leads to glomerular endothelial cell proliferation, recovery from crescentric lesions and an improvement in renal function [53]. A recent study has also implicated changes in basal VEGF-A signalling as an explanation as to why some mice strains are more prone to experimental rapid progressive glomerulonephritis [54]. In 129S2/SvPas mice which are susceptible to anti-GBM disease, VEGFR-2 signalling is dampened compared with resistant C57Bl/6J mice; furthermore blockade of VEGFR-2 is only able to accelerate glomerular damage in C57Bl/6J animals [54].

The impairment of VEGF-A signalling may also be an important molecular pathway in pre-eclampsia, a disorder affecting 3%–5% of pregnant women world-wide and characterized by new-onset hypertension and proteinuria after 20 weeks of gestation [55]. In this condition, circulating levels of sFlt1 are elevated and associated with proteinuria and glomerular injury suggesting that the binding of sFlt1 to VEGF-A may impede its vasoprotective actions at the capillary level [56,57]. In contrast, circulating levels of the angiogenic factor placental growth factor (PlGF) are low in patients with pre-eclampsia [58] and measuring the sFlt1–PlGF ratio has been shown to be an effective diagnostic test to detect women with later onset of pre-eclampsia during the second trimester of pregnancy [59]. However, circulating sFlt1–PlGF may be less useful as a very early predictor of pre-eclampsia during the first trimester of pregnancy, with Baumann et al. [60] finding no difference between pre-eclampsia patients and healthy controls at this time-point. Some studies have found circulating VEGF-A is also reduced in pre-eclamptic women, but others have found contradictory results depending on the method used to assess VEGF-A [58].

The raised circulating sFlt1 levels are thought to originate from the placenta and a recent study showed that women with pre-eclampsia have elevated sFlt1 in placental trophoblasts [61]. Interestingly, the increase in circulating sFlt1 is regulated by raised local VEGF-A in adjacent decidual cells and mice overexpressing Vegfa in the endometrium have increased placental and maternal serum sFlt1 levels leading to pre-eclampsia symptoms including hypertension and proteinuria [61]. Other studies have shown that administration of sFlt1 to normal healthy mice or pregnant rats results in glomerular endothelial cell damage, reduced nephrin expression and proteinuria [62] and injection of recombinant VEGF121 protein can reverse these effects in pregnant rats [63]. In addition, heterozygous knockout mice hypomorphic for Vegfa have incomplete vascular differentiation, with failure of the glomerular capillary endothelium to flatten or form fenestrae, a lesion similar to endotheliosis which is observed in pre-eclampsia [57,64].

A ROLE FOR INHIBITORY VEGF-A ISOFORMS IN THE KIDNEY GLOMERULUS

The complexity of VEGF-A signalling in the glomerulus has increased with the recent discovery of anti-angiogenic VEGF-Axxxb isoforms. Among these, VEGF-A165b is expressed in the apical and basal sides of the epithelium of comma and S-shaped bodies and in the invading glomerular endothelium as evidenced by immunohistochemistry of developing 10–12-week-old foetal human kidneys [65]. In adult kidneys collected from unilateral, unipolar renal carcinoma nephrectomy specimens, glomerular expression of VEGF-A165b is more restricted and found in a sub-population of podocytes and in the parietal epithelium [65]. The function of VEGF-A165b in the glomerulus has begun to be explored using transgenic mouse models. Overexpressing VEGF-A165b specifically in the podocytes of otherwise healthy mice reduces glomerular water permeability with a significantly decreased normalized glomerular ultrafiltration fraction compared with wild-type littermates [66]. This finding was accompanied by a reduction in the amount of endothelial fenestration detected by EM but no changes in proteinuria or glomerular filtration rate [66].

Intriguingly, recent studies indicate VEGF-A165b has therapeutic potential in DN. VEGF-A165b mRNA levels are increased 6-fold in patients with early diabetes with a well-preserved renal function and low-grade proteinuria compared with non-diabetic individuals [67]. This increase is thought to be a protective response in DN as inducible podocyte overexpression of VEGF-A165b in diabetic mice prevents the rises in albuminuria, creatinine clearance, glomerular hypertrophy, mesangial matrix expansion and GBM thickness normally observed in the early stages of DN (assessed 6 weeks after streptozotocin injection) [67]. Systemic injection of recombinant VEGF-A165b in DN also has protective effects. Administration of VEGF-A165b 4–6 weeks after streptozotocin injection for a further 11 weeks reduces urine albumin to creatinine ratios. The improvement in early DN may be due to the increased VEGF-A165b levels providing competition for VEGF-A binding to VEGFR-2. This competition could negate the effect of raised glomerular VEGF-A which can drive the pathophysiology of early DN [22].

In a second set of studies, late treatment with VEGF-A165b 12 weeks following streptozotocin also decreases albumin excretion, along with improvements in GBM thickness [67]. Possible pathophysiological mechanisms which may contribute to the improvement in DN following VEGF-A165b administration may include the attenuation of diabetes-induced glomerular endothelial cell apoptosis, increasing glomerular water permeability and preventing the loss of the endothelial glycocalyx [67]. Interestingly, some of these effects can be attributed to changes in VEGFR-2 signalling; diabetes increases VEGFR-2 phosphorylation in the glomerular endothelium and surprising in this context administration of VEGF-A165b further enhances the phosphorylation of this receptor. In addition, the effects of VEGF-A165b on apoptosis and glomerular water permeability can be blocked using ZM323881, a selective VEGFR-2 inhibitor [67]. The benefit of VEGF-A165b in late DN may be related to the fall in glomerular VEGF-A seen at this time-point. VEGF-A165b signalling through VEGFR-2 may replenish this deficiency and subsequently improve the progression of DN.

VEGF-C AND THE GLOMERULUS

VEGF-A is a member of a larger family of molecules which also contains the ligands VEGF-B, -C, -D and–E and PIGF [9]. Of these, there is some data implicating VEGF-C as having a role in the biology of the glomerulus. The main biological role of VEGF-C is to enhance the growth, survival and migration of adult lymphatic vessels through actions on VEGFR-3, but the ligand also has lesser effects on blood vessels via VEGFR-2 [6870]. VEGF-C is detected by immunohistochemistry in the peripheral cells of the glomerular tuft, presumably podocytes, in human adult renal cortical tissue from patients undergoing nephrectomy for renal carcinoma [71]. VEGF-C and VEGFR-3 mRNAs and proteins are also found in immortalized human podocytes [71,72]. It is suggested that VEGF-C may act in an autocrine fashion to promote podocyte survival. Addition of recombinant VEGF-C reduces the cytotoxicity of cells in serum-starved conditions, an effect which can be prevented by the addition of MAZ51 (3-[[4-(dimethylamino)-1-naphthalenyl]methylene]-1,3-dihydro-2H-indol-2-one), a VEGFR-3 inhibitor [71,72]. Furthermore, neutralization of endogenous podocyte VEGF-C in cells using blocking antibodies enhanced cell apoptosis [71,72]. VEGFR-3 is also detected by immunogold labelling in glomerular endothelial cells of adult human kidneys [73]. Addition of exogenous VEGF-C reduces the passage of macromolecules across glomerular endothelial cell monolayers in vitro [73]. This effect may be in part due to the ability of VEGF-C to alter the composition of the endothelial glycocalyx by promoting the synthesis of hyaluronic acid and increasing the charge density of synthesized glycosaminoglycans which can contribute to reduced protein permeability [34].

ANGIOPOIETINS

A second vascular growth factor family implicated in glomerular biology is the Angpt [74]. Angpt1 is the major physiological ligand which binds and phosphorylates the Tie2 (tyrosine kinase with Ig and EGF homology domain-2) receptor [75]. Angpt1 is critical for the formation of the vasculature during early development with mice with global Angpt1 deletion dying between embryonic day 9.5 to 12.5 due to cardiac trabeculations and widespread vascular defects, fusion of vessels with larger diameters and absence of patterning [76,77]. Moreover many studies indicate that Angpt1 is important in maintaining the stability and permeability of the mature healthy adult vasculature [78,79]. However, this concept has recently been challenged by studies using mice with inducible global deletion of Angpt1 from embryonic day 13.5 [77]. These mice are viable with no overt phenotype or ‘leaky’ vessels leading these authors to postulate that endogenous Angpt1 is primarily important in developmental and pathological situations [77].

Angpt2 has opposing actions to Angpt1 and promotes blood vessel destabilization [80]. This is achieved not only by competitively inhibiting the binding of Angpt1 to Tie2, hence reducing Tie2 activation and signalling [80], but also the activation of integrins [81]. The biological effects of Angpt2 are context-dependent and are particularly dependent on the ambient levels of VEGF-A. Angpt2 leads to vessel regression when VEGF-A is low and angiogenesis in the presence of high levels of surrounding VEGF-A [80].

In the kidney glomerulus (Figure 3A), Angpt1 transcripts are detected in differentiating murine podocytes by in situ hybridization [82]. Angpt1 protein is also expressed in the foot processes of adult human podocytes [83]. Angpt2 is transiently detected in the developing mesangium, as evidenced by studies using a mouse strain expressing the LacZ reporter gene driven by the Angpt2 promoter [84] but is not found in adult healthy murine glomeruli. Tie2 is localized in developing and adult mouse glomerular capillaries [82,85], with some reports showing expression in mouse and rat podocytes in vivo using immunogold techniques [83,86].

Role of Angpt in glomerular physiology and disease

Figure 3
Role of Angpt in glomerular physiology and disease

In health, Angpt1 is expressed in the kidney podocytes to maintain glomerular structure and function (A). During the early phases of diabetic glomerulopathy, there is a decrease in the Angpt1–Angpt2 ratio which is associated with podocyte foot process fusion, basement membrane thickening, mesangial expansion and endothelial cell proliferation leading to albuminuria (B). Transgenic podocyte Angpt2 overexpression in otherwise healthy adult mice leads to endothelial apoptosis and mild albuminuria (C). Experimental repletion of Angpt1 during early DN improves disease progression by increasing eNOS phosphorylation which was associated with reduced glomerular endothelial angiogenesis and decreasing nephrin phosphorylation which may improve podocyte cell structure (D).

Figure 3
Role of Angpt in glomerular physiology and disease

In health, Angpt1 is expressed in the kidney podocytes to maintain glomerular structure and function (A). During the early phases of diabetic glomerulopathy, there is a decrease in the Angpt1–Angpt2 ratio which is associated with podocyte foot process fusion, basement membrane thickening, mesangial expansion and endothelial cell proliferation leading to albuminuria (B). Transgenic podocyte Angpt2 overexpression in otherwise healthy adult mice leads to endothelial apoptosis and mild albuminuria (C). Experimental repletion of Angpt1 during early DN improves disease progression by increasing eNOS phosphorylation which was associated with reduced glomerular endothelial angiogenesis and decreasing nephrin phosphorylation which may improve podocyte cell structure (D).

ANGIOPOIETINS AND DIABETIC NEPHROPATHY

Several studies have examined the expression of Angpt in glomerular disease (Table 2), with the majority of studies focusing on DN (Figure 3B). In rats injected with streptozotocin, whole-kidney Angpt1 and Angpt2 mRNA and protein increase 4 weeks after injection, but after 8 weeks Angpt1 levels diminish, whereas Angpt2 remains elevated [87]. In another study, whole glomeruli or Vegfr2/GFP+ glomerular cells (presumed to be endothelia) isolated from mice administered with streptozotocin contain elevated Angpt2 mRNA levels compared with non-diabetic animals [77]. This finding is consistent with studies showing raised Angpt2 levels in cultured murine kidney endothelial cells exposed to hyperglycaemia [88]. Angpt1 mRNA levels are not altered in Vegfr2/GFP glomerular cells (presumed to contain podocytes and mesangium) or whole glomeruli, although Vegfa levels rose [77]. ANGPT2 mRNA is also elevated in isolated glomeruli from diabetic patients compared with live donor kidneys with no change in ANGPT1 [86] and high circulating Angpt2 levels are found in patients with type 2 diabetes which correlates with haemoglobin A1c [89]. Transgenic mouse studies have also shown that raised Angpt2 leads to features of DN. Inducible podocyte overexpression of Angpt2 in otherwise normal healthy mice leads to blood vessel destabilization manifested as albuminuria and glomerular endothelial apoptosis with significant decreases in VEGF-A and nephrin [90] (Figure 3C). In contrast, our group has shown that in the very early stages of DN, 3 weeks after injection of streptozotocin in mice, glomerular Angpt1 mRNA decreases in diabetic mice, with no significant changes in Angpt2 mRNA [86]. Additionally, ANGPT1 mRNA was significantly down-regulated in high glucose-treated podocytes compared with normal glucose-treated cells [86]. Overall, these observations are consistent with the contention that a decreased ratio of Angpt1–Angpt2 might play a role in the progression of glomerular disease in DN.

Table 2
Alterations of Angpt in glomerular disease

↑, increased; ↓, decreased

Disease/Animal modelAngiopoietin expressionReferences
Type 1 DN Early stages: ↓ Angpt1 glomerular mRNA in murine DN [77,86
 Late stages: ↑ Angpt2 glomerular mRNA in murine and human DN, overexpression of Angpt2 in otherwise normal healthy adult mice results in proteinuria and glomerular endothelial apoptosis [77,86,90
Anti-GBM glomerulonephritis ↑ Angpt2 and ↓ Angpt1 glomerular protein expression associated with glomerulosclerosis and loss of endothelium [95
Daunorubicin-induced glomerulonephritis ↑ Angpt2 and ↓ Angpt1 glomerular mRNA and protein as glomerulosclerosis progresses [96
Thy-1 model ↑ Angpt1 and ↑Angpt2 glomerular mRNA and protein expression at peak of capillary aneurysm formation and destruction [97
Disease/Animal modelAngiopoietin expressionReferences
Type 1 DN Early stages: ↓ Angpt1 glomerular mRNA in murine DN [77,86
 Late stages: ↑ Angpt2 glomerular mRNA in murine and human DN, overexpression of Angpt2 in otherwise normal healthy adult mice results in proteinuria and glomerular endothelial apoptosis [77,86,90
Anti-GBM glomerulonephritis ↑ Angpt2 and ↓ Angpt1 glomerular protein expression associated with glomerulosclerosis and loss of endothelium [95
Daunorubicin-induced glomerulonephritis ↑ Angpt2 and ↓ Angpt1 glomerular mRNA and protein as glomerulosclerosis progresses [96
Thy-1 model ↑ Angpt1 and ↑Angpt2 glomerular mRNA and protein expression at peak of capillary aneurysm formation and destruction [97

Subsequent studies using transgenic mice have helped to reveal the importance of Angpt signalling in modulating the glomerular response following DN. In male diabetic mice with a global deletion of Angpt1 from embryonic day 16.5 (to circumvent any adverse effects on early vascular development), loss of Angpt1 increases albuminuria, mesangial matrix expansion and glomerulosclerosis compared with wild-type controls 20 weeks after induction of diabetes [77]. These experiments suggest that local glomerular Angpt1 production could potentially confer protection against diabetic glomerular injury.

To examine this possibility further, we attempted to restore the Angpt1 deficiency found in early diabetic glomerulopathy using transgenic mice [86]. Podocyte Angpt1 repletion for 10 weeks in diabetic mice leads to an improvement in the permeability of the glomerular filtration barrier with a 70% reduction in albuminuria [86]. Angpt1 repletion in DN also leads to a dampening in diabetes-induced VEGF-A signalling. This combination of high Angpt1 and low VEGF-A signalling in DN stabilizes the glomerular vasculature by reducing the proliferation of glomerular endothelial cells normally seen in the early stages of DN [27] and prevents vascular leakage which is manifested as a reduction in albumin excretion [86].

Overexpression of Angpt1 in diabetic mice increases the phosphorylation of eNOS on Ser1177 [86], an effect which may increase NO [91] and subsequently inhibit angiogenesis and blood vessel permeability to improve vascular stability [39,41].

Angpt1 repletion also reduces diabetes-induced nephrin phosphorylation [86] which may be a direct effect of Angpt1 on podocyte cells (Figure 3D). A reduction in nephrin phosphorylation can be beneficial in DN as it may prevent the degradation of nephrin protein and help to maintain the podocyte silt diaphragm. Alternatively, as nephrin phosphorylation in podocytes can alter the podocyte cytoskeleton with a decrease in stress fibres and an increase in lamellipodia [92], the overexpression of Angpt1 in DN may improve podocyte cell structure and subsequently lead to a more intact glomerular filtration barrier.

These observations suggest a promising therapeutic strategy in DN could be to manipulate Angpt levels in the early stages of diabetic kidney disease. However, to-date, only one study has shown that systemic delivery of cartilage oligomeric matrix protein–Angpt-1 (COMP-Angpt-1; a modified form of Angpt-1) by adenoviral transduction of hepatocytes reduces renal fibrosis in db/db mice. However, this strategy also significantly improves hyperglycaemia, which could itself, at least partly, account for the amelioration of diabetes [93]. An interesting study has recently shown that a small-molecular inhibitor of vascular endothelial–protein tyrosine phosphatase (VE–PTP), which negatively regulates Tie2 activation, can prevent features of diabetic retinopathy [94]. Future studies should evaluate whether this could be a promising strategy for slowing DN.

ANGIOPOIETINS AND OTHER GLOMERULAR NEPHROPATHIES

The expression of Angpt1 and Angpt2 has been examined in several other glomerular diseases. In progressive glomerulonephritis induced by injection of anti-GBM in mice glomerular expression of Angpt1 is reduced, whereas Angpt2 is elevated [95]. These alterations are associated with glomerulosclerosis and loss of endothelium and capillary loops [95]. In rats with glomerulonephritis induced by daunorubicin, the appearance of glomerulosclerosis correlates with decreased Angpt1–Angpt2 expression ratio [96]. The angiopoietin family may play an important role in the repair of the glomerulus following injury; in the rat Thy-1 model of glomerulonephritis, both Angpt1 and Angpt2 gene and protein expression are increased in glomeruli at the peak of capillary aneurysm formation and destruction [97]. It has been postulated these increased levels may co-ordinate an environment to promote glomerular repair [97]. Overall, this data suggest that altered angiopoietin expression may play an important role in the progression of these glomerular nephropathies. However, functional studies such as those undertaken for DN are required using transgenic mice to firmly establish this in the future.

VASCULAR GROWTH FACTORS AND THE PERITUBULAR MICROVASCULATURE

Glomerular disease is often accompanied by major changes in the tubulointerstitium featuring tubular atrophy, inflammation and fibrosis which contribute to kidney disease progression. These pathophysiological changes are associated with a loss of the peritubular microvasculature leading to the hypothesis that revascularization in the tubulointerstitium may be a promising therapeutic avenue for chronic kidney disease [98]. Peritubular capillaries express VEGFR-2 [99], VEGFR-3 [100] and Tie2 [85] suggesting that their biology can be modulated by ligands of the VEGF and Angpt families; a detailed description of vascular growth factor signalling in peritubular capillaries is beyond the scope of the present article and is described in recent reviews [101,102]. Administration of recombinant VEGF-A121 in rat remnant kidneys increases peritubular capillary number which attenuates fibrosis and improves renal function [103]. Adenoviral administration of a recombinant form of Angpt1 reduces chronic loss of peritubular capillaries in murine nephropathy induced by folic acid but also enhances kidney fibrosis and inflammation [104]. More recently, Huang et al. [100] reported that recombinant VEGF-C improves the severity of murine polycystic kidney disease. VEGF-C remodels the vasculature surrounding cysts, reduces macrophages infiltrate and improves renal function [100]. Taken collectively, these studies suggest that treatments using vascular growth factors for glomerular disease may heal not only the filtration barrier but also prevent the tubulointerstitial changes involved in the progression of chronic kidney disease.

SUMMARY

A tightly controlled milieu of vascular growth factors is required for the development and maintenance of a healthy glomerular filtration barrier. Disruption of vascular growth factor signalling leads to various types of glomerular disease. Manipulation of local and systemic VEGF-A and Angpt remain attractive therapeutic targets for patients with glomerular disease, particularly in combination with therapies that restore the kidney peritubular capillaries. Future directions may involve taking synergistic approaches which target multiple vascular growth factors or novel targets such as VE–PTP.

FUNDING

This work was supported by Diabetes UK [grant numbers 08/0003695, RD04/0002860 and 13/0004763 (to L.G., D.A.L. and A.S.W.)]; the Biotechnology and Biological Sciences Research Council [grant number S13745 (to L.G.)]; the European Foundation for the Study of Diabetes /Servier (to L.G.); the Kidney Research UK Senior Non-Clinical Fellowship [grant number SF1/2008]; the Medical Research Council New Investigator Award [grant number MR/J003638/1]; the Great Ormond Street Children's Charity (to D.A.L.); and grant support from the Manchester Biomedical Research (to A.S.W.).

Abbreviations

     
  • Angpt

    angiopoietins

  •  
  • DN

    diabetic nephropathy

  •  
  • eNOS

    endothelial nitric oxide synthase

  •  
  • GBM

    glomerular basement membrane

  •  
  • NO

    nitric oxide

  •  
  • sFlt1

    soluble VEGFR-1

  •  
  • Tie2

    tyrosine kinase with Ig and EGF homology domain-2

  •  
  • VEGF

    vascular endothelial growth factor

  •  
  • VE–PTP

    vascular endothelial–protein tyrosine phosphatase

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