Role of the eNOS-NO System in Regulating the Anti-Proteinuric Effects of VEGF Receptor 2 Inhibition in Diabetes

Andrew Advani,Kim A Connelly,Kerri Thai,Richard E Gilbert,Suzanne L Advani

doi:10.1016/j.jcjd.2013.08.135

Abstract

Since the original description over a decade ago of the upregulation of the VEGF/VEGFR-2 system in the diabetic kidney, there has been intense interest in the pathogenetic role of this system in renal decline and its amenability to therapeutic interventions. Recently, it has become apparent that subtle perturbations in intraglomerular VEGF/VEGFR-2 signalling or in the influencing microenvironment can profoundly affect renal function, resulting in the apparently paradoxical observation that VEGF blockade attenuates proteinuria development in experimental diabetes despite exerting the opposite effect under other circumstances. In the present study, we sought to explore the role of eNOS-NO activity in regulating the differential response to VEGF blockade in the diabetic and non-diabetic settings. In a rodent model of accelerated renal injury, the transgenic (mRen-2)27 (Ren-2) rat, VEGFR-2 inhibition with the small molecule vandetanib resulted in an increase in urine protein excretion preceding a subsequent rise in systolic blood pressure. When compared to their normoglycemic counterparts, diabetic Ren-2 rats exhibited an increase in the renal expression of eNOS and in urinary excretion of nitric oxide (NO) metabolites. In contrast to the heavy proteinuria observed with vandetanib in non-diabetic TGR(mRen-2)27 rats, VEGFR-2 inhibition reduced urine protein excretion in diabetic animals, despite a comparable magnitude of histological injury. However, proteinuria was markedly increased by concomitant treatment of diabetic Ren-2 rats with vandetanib and the nitric oxide synthase inhibitor L-NAME. These observations highlight the pivotal role that the eNOS-NO system plays in regulating the biological response to VEGF within the glomerulus especially under diabetic conditions.

Highlights

Reduction in New Onset Diabetes After Transplant (NODAT) with Erythropoietin-Stimulating Agents, a Case Control Study TESS MONTADA-ATIN*, DIANA CHOI, MINNA WOO, RAVI RETNAKARAN, MICHAEL HUANG, RAMESH PRASAD, JEFFREY S
Studies have shown that erythropoietin-stimulating agents (ESA) protect mice against the development of diabetes through direct effects on pancreatic ß cells
Multivariate logistic regression analysis was performed to determine factors independently associated with New-onset diabetes mellitus after transplantation (NODAT) including age, body mass index, acute rejection, donor source and random blood sugar (RBS) at discharge

Summary

Introduction

Reduction in New Onset Diabetes After Transplant (NODAT) with Erythropoietin-Stimulating Agents, a Case Control Study TESS MONTADA-ATIN*, DIANA CHOI, MINNA WOO, RAVI RETNAKARAN, MICHAEL HUANG, RAMESH PRASAD, JEFFREY S. New-onset diabetes mellitus after transplantation (NODAT) adversely affects graft and patient survival. We performed a case-control analysis of patients with NODAT who received a first live or deceased donor renal allograft, comparing those with exposure to an ESA versus those without such exposure.

Results

Conclusion