VEGF therapy for the kidney: emerging strategies

Abstract

Renovascular disease (RVD), which is prevalent in the elderly, significantly increases cardiovascular risk and can progressively deteriorate renal function. The loss of renal function in patients with RVD is associated with a progressive dysfunction, damage, and loss of renal microvessels, which can be combined with decreased renal bioavailability of vascular endothelial growth factor (VEGF) and a defective vascular repair and proliferation. This association has been the impetus for recent efforts that have focused on developing methods to stop the progression of renal injury by protecting the renal microvasculature. This mini-review focuses on recent studies supporting potential applications of VEGF therapy for the kidney and discusses underlying mechanisms of renoprotection.

INTRODUCTION

The kidney is a highly vascularized organ in which the renal microvasculature not only serves the metabolic demands of the kidney, but also plays a key role for whole body homeostasis of blood pressure, body fluid and electrolyte balance, pH, calcium metabolism, and erythropoiesis. Microvascular (MV) rarefaction is observed in renal pathologies and can be structural or functional: anatomical loss of the microvessels or functional loss of the microvessels with no anatomical change, respectively (33). Several studies have shown that renal MV rarefaction, which entails dysfunction and remodeling, are universal features in acute and chronic renal disease from different etiologies (19, 20) that progress and evolve along with renal dysfunction and injury (20). Clinical and experimental studies have also shown that damage of the small renal vessels may precede and predict the decline in renal function in hypertension, diabetes, and obesity (2, 9, 28, 35), which are major causes of chronic renal disease. Altogether, these compelling data support a plausible cause-and-effect relationship between MV rarefaction and renal injury and offer a rationale for MV protection as a therapeutic approach.

Chronic renovascular disease (RVD) is a progressive condition initially caused by unilateral or bilateral obstruction of the main renal artery or primary bifurcations. RVD is caused by atherosclerotic renal artery stenosis in more than 90% of cases (45), affects 9–11% of the adults in the United States (41, 46, 47), and may lead to or intensify cardiovascular and renal pathologies. Indeed, patients with RVD usually suffer from hypertension and higher cardiovascular morbidity and mortality, and they are more prone to develop chronic kidney disease (CKD) by up to 25% (45). Using a clinically relevant model of RVD in swine, studies from our laboratory showed that the progressive decline in the function of the stenotic kidney (e.g., reduced renal blood flow and glomerular filtration) and renal injury in RVD associates with a progressive renal MV rarefaction that is exacerbated by defective mechanisms of MV repair and proliferation in the kidney (10–12, 14, 15). Furthermore, we showed that structural and functional renal MV rarefaction in RVD is largely driven by progressively reduced renal bioavailability of vascular endothelial growth factor (VEGF), an endogenous angiogenic cytokine with prominent roles in MV proliferation and repair that maintains vascular networks in every tissue, including the kidney (18). The loss of VEGF is followed by altered downstream angiogenic signaling (14, 29, 52), which subsequently contributes to the defective renal recruitment and homing of cell progenitors in RVD. Our previous work (14, 15) supports the idea that disruption of this endogenous mechanism of tissue healing in RVD significantly contributes to progression of the disease.

Recent studies support the potential for VEGF therapy as a tool to restore renal MV architecture and function and slow the progression of renal injury in different models of renal disease (3, 10–13, 31, 32). This concise review will focus on potential mechanisms and novel applications of VEGF therapy for the kidney.

VEGF in the kidney.

VEGF is a proangiogenic and prosurvival factor for endothelial cells that promotes cell division, survival (22, 23), mobilization of endothelial progenitor cells (EPCs) (53), and vascular proliferation. VEGF plays a central role in angiogenesis, an important process not only during organ development, but also in the response to tissue ischemia (18), during which it maintains and repairs MV networks in virtually every organ. A functional vasculature is vital for maintaining the kidney’s normal physiological functions, and the importance of VEGF in this process is highlighted by studies showing that VEGF inhibition associated with the development of hypertension, podocyte loss (25), and renal injury (17). Furthermore, a significant reduction in VEGF availability is observed in renal pathologies associated with chronic reductions in blood flow, including RVD (29), CKD of different etiologies (e.g., diabetes and hypertension) (19, 20), and progressive glomerulopathies (42).

VEGF therapy: recent studies.

To counteract tissue hypoxia, the microvasculature adapts to local metabolic conditions partly through angiogenesis, which entails sprouting of new vessels from preexisting ones (20). Unlike in conditions of acute ischemia, tissues exposed to chronic ischemia not only often have significant MV damage, but also an impaired angiogenic response that results, in part, from decreased availability of VEGF and altered downstream signaling (29, 38). On the basis of these observations, the idea of VEGF therapy to recover MV proliferation and repair has been tried in different pathological conditions, such as neurodegenerative diseases (16), placental abnormalities (24), peripheral neuropathies (49), peripheral artery disease (44), myocardial ischemia (1, 40), and renal ischemia, as occurs in RVD (30, 39, 51). However, not until recently has more attention turned toward the potential of VEGF therapy for the kidney.

Studies have reported the benefits of VEGF therapy in several experimental models of renal disease (3, 31, 32). For example, in both the remnant kidney model and a rodent model of CKD, systemic or subcutaneous injection of the VEGF successfully preserved the MV structure and density by stimulating EPCs, which subsequently stabilized renal function and attenuated disease progression (3, 31, 32). These studies support the feasibility of VEGF therapy as a tool to preserve renal vascular integrity. We recently demonstrated the feasibility and therapeutic efficacy of intrarenal administration of recombinant-human (rh)-VEGF through the main renal artery, distal to the vascular obstruction (10, 11) in a clinically relevant swine model of chronic RVD. Both preventive (10) and interventional (11) intrarenal administration of rh-VEGF produced similar renoprotective effects on MV rarefaction and stenotic kidney hemodynamics and function, indicating that newly formed vessels are likely functional. Along with improved vessel structure and function, fibrosis was also attenuated, suggesting that intrarenal VEGF therapy may attenuate the progression of renal injury in RVD, even when administered at an advanced stage of the disease (Fig. 1). However, one limitation of this approach is that intravenous, intrarenal, or subcutaneous VEGF delivery may potentially affect other organ systems besides the kidney. In addition, the short half-life and high susceptibility to degradation of VEGF in vivo may require repeated intrarenal injections to achieve significant therapeutic benefits. Indeed, previous studies (1, 16, 24, 40) showed that repeated or continuous VEGF therapy directly to the target site was required for efficacy, underscoring the need for sustained VEGF release (21). Repeated VEGF therapy may further increase the potential for untoward side effects in other organ systems. Therefore, to improve efficacy and reduce potential side effects, new strategies that target VEGF specifically to the kidney may address these concerns and help to advance the field.

Fig. 1.

Schematic flow chart describing mechanisms of renal injury in renovascular disease and proposed mechanism of renoprotection by vascular endothelial growth factor (VEGF) therapy. Accompanied by a three-dimensional micro-CT reconstruction of the renal microcirculation (A and B, top) and a representative renal cross section showing renal fibrosis in the stenotic kidney (trichrome, ×20, A and B, bottom). MV, microvascular; ELP, elastin-like polypeptides; EPC, endothelial progenitor cells; RBF, renal blood flow; GRF, glomerular filtration rate.

Elastin-like polypeptides: a novel tool for VEGF delivery.

Elastin-like polypeptides (ELPs) are synthetic proteins based on human elastin that can be used as efficient drug delivery vectors because of their long plasma half-life (5, 34) and low immunogenicity (37, 43). Additionally, ELPs can be modified to the desired size and transition temperature (48) to improve tissue penetration and targeting, and they can be linked to virtually any therapeutic proteins or peptides (5–8, 36, 37).

Recently, Chade et al. (12, 13) developed a novel biopolymer-delivered VEGF construct by fusing VEGF to an ELP carrier (ELP-VEGF). The ELP-VEGF construct is active in vitro and in vivo, accumulates mostly in the kidney regardless of the administration route (12, 13), and is detectable in the circulation for a longer period of time with a slower renal clearance than unconjugated VEGF (21). In addition, we demonstrated that a single intrarenal (12) or systemic (13) injection of ELP-VEGF in a swine model of RVD induced renoprotective effects that were superior to unconjugated VEGF. These renoprotective effects were associated with improved renal VEGF signaling and augmented expression of factors involved in mobilization and homing of cell progenitors (13) (Fig. 1). Therefore, it is possible that the long-term, sustained effects of ELP-VEGF therapy were largely driven by stimulating progenitor cell recruitment to the kidney, leading to a proangiogenic milieu that restored endogenous mechanisms of vascular repair and proliferation, consequently resulting in a prolonged renoprotection in RVD. Importantly, intrarenal or systemic ELP-VEGF therapy did not induce any off-the-kidney effects (13). Overall, these studies demonstrated the therapeutic potential of using ELP as a renal vector for delivery of VEGF, and highlighted the success of ELP-VEGF therapy to target the kidney, protect the renal microcirculation, and preserve renal function more efficiently than unconjugated VEGF.

More recently, Bidwell et al. (4) developed a novel kidney-targeted version of an ELP carrier (KTP-ELP) to achieve even greater renal specificity (4). Uptake by human renal cells (glomerular microvascular endothelial cells, podocytes, and proximal tubular epithelial cells) of the KTP-ELP construct in vitro was higher than untargeted ELP, and acute or chronic administration of KTP-ELP in vivo resulted in greater renal accumulation than ELP with no adverse effects on renal function in rodent or swine models (4), demonstrating the specificity and safety of the KTP-ELP carrier regardless of the species. Ongoing efforts aim to fuse KTP-ELP to VEGF to augment renal VEGF targeting; future studies will determine whether KTP-ELP-VEGF improves renal function in RVD as efficiently as ELP-VEGF or more, but with the advantage of minimizing the potential for off-target effects regardless of the route of administration.

Conclusions.

VEGF therapy for the kidney is a feasible strategy that may be honed and built upon. It is promising that many of the findings and new methods of delivering VEGF to the injured kidney have been characterized in a clinically relevant swine model of RVD, whose similarities to humans may increase the potential for a “bench-to-bedside” transition of therapeutic angiogenesis in the near future. Furthermore, the success of VEGF therapy in inducing protective effects on the microvasculature in several clinical pathologies (26, 27, 50) supports the notion that it may be beneficial for clinical use in other diseases. Potential clinical applications of VEGF therapy will be further supported by future preclinical studies on outcomes of VEGF therapy in relation to biological characteristics, such as animal age and sex. Finally, since damage of the renal microcirculation is universally present in chronic renal disease (20), the road ahead may offer opportunities for application to renal diseases of different etiologies, and, ideally, at different stages of severity, although future studies are necessary to determine the effectiveness of VEGF therapy in all renal disease. Such studies may help to identify the “window of opportunity” by which therapeutic angiogenesis can successfully halt or reverse the progression of renal injury.

GRANTS

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R41 DK-109737 from the National Institutes of Health, Grant 18490005 from the American Heart Association, and a grant from intramural research support program from the University of Mississippi Medical Center (A. R. Chade).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

E.G. and A.R.C. prepared figures; E.G. and A.R.C. drafted manuscript; E.G. and A.R.C. edited and revised manuscript; E.G. and A.R.C. approved final version of manuscript.