Abstract: TH-PO080
Depletion of Gprc5a Promotes Development of Diabetic Nephropathy
Session Information
- Glomerular: Basic/Experimental Pathology - I
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Glomerular
- 1002 Glomerular: Basic/Experimental Pathology
Authors
- Patrakka, Jaakko, Karolinska Institutet, Huddinge, Sweden
- Lal, Mark, AstraZeneca, Gothenburg, Sweden
- Zambrano Sevilla, Sonia, None, Seville, AND, Spain
Background
Renal glomeruli are the primary target of injury in diabetic nephropathy (DN). In the glomerulus, damage to podocyte cells plays a critical role in the disease progression. Transforming growth factor beta (TGF-β) signaling is involved in the pathogenesis but mechanisms regulating this pathway in podocytes are poorly understood. G-protein coupled receptors (GPCRs) have been the most successful protein class for drug discovery as 20-40% of currently clinically approved drugs are targeting them. In this study, we investigated glomerular GPCRs in DN with the aim of identifying novel molecular targets for pharmaceutical intervention.
Results
We performed high throughput molecular profiling of GPCRs in human glomeruli and identified an orphan GPCR, Gprc5a, as a novel highly podocyte-specific molecule whose expression was significantly down-regulated in patients with DN. Inactivation of Gprc5a in mouse resulted in thickening of the glomerular basement membrane and activation of mesangial cells, which are two hallmark features of DN in humans. Gprc5a-deficient animals were susceptible to diabetic glomerular damage as demonstrated by higher albuminuria and more severe histological changes after induction of diabetes with streptozotocin. Mechanistically, we show that Gprc5a modulates TGF-β signaling pathway in podocytes through activation of epidermal growth factor receptor (EGFR).
Conclusion
We conclude that depletion of Gprc5a promotes the progression of DN. Gprc5a can provide us a possibility to develop pharmaceutical tools to manipulate pathogenic signaling pathways in a podocyte-specific manner.
Funding
- Commercial Support –