The vasculature in diabetic nephropathy: all tied up?

Diabetic nephropathy (DN) is the leading cause of ESRD in the United States, and its global occurrence is rising rapidly. As evidencedby thewide spectrumofdebilitatingmacroand microvascular complications that patients eventually experience, the vascular endothelium is a prominent target of longstanding diabetes. In the hunt for breakthrough discoveries that could someday transform the treatment of DN, signaling pathways that regulate the form and functions of blood vessels have recently garnered significant attention. In this issue of JASN, Dessapt-Baradez et al. have deployed a combination of conditionally transgenic mice and human DN biopsy studies to advance the proposition that therapies targeting the vasculature may ameliorate DN.1 In 2001, the National Institutes of Health initiated the Animal Models of Diabetic Complications Consortium to tackle the well known resistance of inbred mouse strains to DN and other diabetic manifestations, a limitation that had severely impeded investigation of themolecular pathogenesis underlying progressive diabetes. The field of vascular research in DN received a substantial boost in 2006 and 2007 when two groups reported in JASN that diabeticmice null for endothelial nitric oxide synthase (eNOS2/2) recapitulated major structural and functional features of advanced human DN.2,3 The enzyme eNOS is highly specifically expressed in the endothelium and is responsible for producing the vasodilator nitric oxide, which is thought to contribute to vascular homeostasis. Loss of eNOS-derived nitric oxide activity has been observed in diabetic patients well before the onset of severe end-organ complications (reviewed by De Vriese et al.4). Although the regulation of eNOS is complex,5 two important growth factors upstream of eNOS have been implicated in DN—vascular endothelial growth factor-A (VEGF-A) and, more recently, angiopoietins-1 and -2 (Angpt-1 and -2). VEGF-A and Angpt-1 are constantly secreted by healthy podocytes and signal distinct receptors expressed on the surface of endothelial cells, VEGFR1/2 and Tie-2, respectively. As a potentially useful oversimplification, VEGF-A signals through VEGFR2 to induce angiogenesis and to attenuate barrier function, the latter activity accounting for VEGF’s original name of “vascular permeability factor.”6 Angpt-1 activates Tie-2 to stabilize newly sprouted vessels, and, importantly, it prevents vascular leakage and enhances basal microvascular barrier function.7–9 Systemic administration of the anti-VEGF antibody bevacizumab can produce glomerular endotheliosis, proteinuria, and thrombotic microangiopathy, indicating an essential role for VEGF in the maintenance of glomerular architecture and health.10 No comparable clinical data regarding Angpt-1 inhibition exist because drugs targeting this pathway are investigational. But unlike with VEGF-A, conditional knockout mice suggest that Angpt-1 is dispensable in the mature glomerulus.11 The available data for VEGF-A in DN appear to be conflicting. For example, VEGF-A has been reported to be upregulated12 or downregulated13 in human DN biopsies. Deletion of VEGF from podocytes has been shown to exacerbate DN in the streptozotocin (STZ) model of type 1 diabetes by Sivaskandarajah et al.,14 whereasVeron et al.15 reported that inducible overexpression of VEGF in the podocyte causes severe nodular glomerulosclerosis in the STZmodel. Similar to the results of Veron et al., the Gnudi laboratory showed that podocyte overexpression of a naturally occurring VEGF inhibitor called sFlt-1 improves DN.16 An attempt to synthesize the VEGF literature in DN is beyond the current scope of this editorial, but in contrast, the current report from DessaptBaradez et al. adds to two prior independent experimental studies that collectively demonstrate a renoprotective role for Angpt-1 in DN. In 2007, a group led by Park used a systemic viral gene therapy approach to achieve excess circulating Angpt-1 for 8 weeks starting during young adulthood in db/db type 2 diabeticmice.17 They found that renal levels of inflammatory adhesion proteins and profibrotic signaling molecules were reduced by Angpt-1 treatment. Urinary albumin excretion was reduced from approximately 150 mg/d to approximately 100 mg/d, and histopathologic changes, namely mesangial matrix expansion and glomerular basement membrane thickness, were similarly reduced by Angpt-1. The study was somewhat confounded because the Angpt-1 group also exhibited less severe elevation of fasting blood glucose levels and less visceral adiposity. In 2011, the Quaggin laboratory genetically deleted Angpt-1 at the end of in utero development and administered STZ 1–3 weeks after weaning.11 Unlike Lee et al. they observed no Angpt-1–dependent effect Published online ahead of print. Publication date available at www.jasn.org.