Abstract: TH-PO699
Neuropeptide Y Is a Novel Modulator of Podocyte Function and Its Loss Is Protective in Several Models of Albuminuric Renal Disease
Session Information
- Diabetes Mellitus and Obesity: Basic - Experimental - I
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Diabetes
- 501 Diabetes Mellitus and Obesity: Basic - Experimental
Authors
- Lay, Abigail Charlotte, University of Bristol, Bristol, United Kingdom
- Hurcombe, Jenny, University of Bristol, Bristol, United Kingdom
- Ross, Eleanor W, MRC Harwell Institute, Oxfordshire, United Kingdom
- Barrington, Fern, University of Bristol, Bristol, United Kingdom
- Welsh, Gavin Iain, University of Bristol, Bristol, United Kingdom
- Coward, Richard, University of Bristol, Bristol, United Kingdom
Background
Neuropeptide Y (NPY) is one of the most abundant peptides of the central and peripheral nervous systems, with a key role in energy homeostasis. However its function in the glomerulus has not previously been reported. Using a non-biased transcriptomic approach we discovered that NPY was highly significantly down-regulated in both human and mouse conditionally immoralised podocytes when rendered insulin resistant mimicking a diabetic environment (25-fold down regulated p=10-125). Data from the nephromine database, comparing diabetic nephropathy (DN) patient groups, suggests this also occurs in human glomeruli. We therefore went on to study the biological importance of NPY on podocyte and glomerular biology.
Methods
Conditionally immortalized human and mouse podocytes were studied in vitro to determine NPY receptor signalling. For our in vivo investigations we studied wild-type (WT) 129Sv and NPY-deficient (NPY-/-) 129Sv mice, comparing two models of albuminuric renal injury; adriamycin nephropathy and streptozotocin (STZ)-induced diabetic nephropathy (DN).
Results
NPY rapidly signals to human and mouse podocytes through the PI3K and MAPK pathways and this is blocked in the presence of the Y2 receptor antagonist BIIE0246, indicating these responses are NPY2R-dependent. NPY also causes a rapid increase in intracellular calcium, which in turn promotes the nuclear translocation of NFAT. Interestingly, in contrast to WT controls, NPY-/- mice are protected from albuminuria 6 months after the induction of STZ-DN (a 4-fold increase in albuminuria is observed in WT mice, p=0.036 WT citrate vs STZ. No significant increase in albuminuria is observed in NPY-/- mice, p=0.6828 NPY-/- citrate vs STZ). Similarly, 14 days after the induction of adriamycin nephropathy, NPY-/- mice had a significantly (p=0.0172) lower level of albuminuria than WT controls.
Conclusion
NPY has a novel role in regulating podocyte and glomerular biology. Our data suggests that in diabetic nephropathy and insulin resistant states its glomerular secretion is supressed to protect against disease progression.