ECE2017 Eposter Presentations: Diabetes, Obesity and Metabolism Diabetes complications (102 abstracts)
PDE5i preserves renal function in models of Diabetic Nephropathy: from bench to bedside
Riccardo Pofi 1 , Daniela Fiore 1 , Tiziana Feola 1 , Elisa Giannetta 1 , Giulia Le Grazie 1 , Carla Di Dato 1 , Daniele Gianfrilli 1 , Biagio Barbano 2 , Mary A. Venneri 1 , Andrea Lenzi 1 & Andrea M. Isidori 1
1Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy; 2Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy.
One third of diabetic patients suffer from Diabetic Nephropathy (DN) that leads to end-stage renal disease (ESRD). The molecular pathways involved remain underexplored. We showed that chronic phosphodiesterase-5 inhibition (PDE5i) improve vascular inflammation [1] and tissue remodelling, reducing proteinuria [2] in murine diabetes. Our aim was to investigate the effect of PDE5i on animal and human models of DN.
Materials and methods: 16 mice were randomly assigned to four groups: control (CTRL), sildenafil (SILD), streptozotocin (STZ), STZ+SILD. Renal Doppler ultrasound (RDU) was performed at baseline and after 6 weeks. Renal resistive index-RRI, GFR (ml/min), mean Blood Pressure-MBP (mmHg) were recorded. FITC-dextran (2 mg/kg) was used to assess permeability and integrity of renal endothelium. 30 type 2 diabetic (T2DM) patients were randomly assigned to placebo (PLC) or tadalafil (TAD) 20 mg/die. RDU was performed at baseline and after 5 months.
Results: All STZ-treated animal developed diabetes. Compared to the STZ, STZ+SILD preserved renal function. Specifically, SILD treatment prevented: (a) the ESRD-related hypertension (MBP, mean change from baseline: STZ 28.72±3.76, STZ+SILD −9.46±4.84, P=0.002); (b) the fall in GFR (STZ −15.24±3.67, STZ+SILD 17.79±3.67; P=0.005); (c) the rise in RRI (STZ 0.10±0.03, STZ+SILD −0.07±0.03; P=0.026); (d) the reduction in FITC-perfuse vessels (microvascular density mean change STZ -2.45±0.48, STZ+SILD 2.1±0.49, P=0.005); (e) pericytes detachment from endothelial cell coverage (STZ 10%, STZ+SILD 60%, P<0.01). TAD treated T2DM patients: (a) improved renal microcirculation (RRI: PLC 0.01±0.04, TAD −0.04±0.03; P=0.014); (b) decreased diastolic pressure (PLC 0.71±9.00, TAD −6.00±9.11; P=0.012).
Conclusions: PDE5i treatment reversed ESRD in a hyperglycemic mouse model targeting renal pericytes and restoring intrarenal haemodynamics. In humans, PDE5i improved renal microcirculation slowing worsening of renal function in course of DN. PDE5i could disclose novel treatment strategies for DN.
References: 1. Venneri MA Chronic inhibition of PDE5 limits pro-inflammatory monocyte-macrophage polarization in streptozotocin-induced diabetic mice. Plos One 2015.
2. Sonneveld R Sildenafil prevents podocyte injury via PPAR-γ-mediated TRPC6 inhibition. J Am Soc Nephrol. 2016.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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