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Abstract: FR-PO194

A Novel Role for NPY-NPY2R Signalling in Albuminuric Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Lay, Abigail Charlotte, University of Bristol, Bristol, United Kingdom
  • Barrington, Fern, University of Bristol, Bristol, United Kingdom
  • Hurcombe, Jenny, University of Bristol, Bristol, United Kingdom
  • Mountjoy, Edward, Wellcome Sanger Institute, Hinxton, United Kingdom
  • Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
  • Atan, Denize, University of Bristol, Bristol, United Kingdom
  • Nelson, Robert G., National Institutes of Health, Phoenix, Arizona, United States
  • Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, U.Michigan, Ann Arbor, Michigan, United States
  • Welsh, Gavin Iain, University of Bristol, Bristol, United Kingdom
  • Coward, Richard, University of Bristol, Bristol, United Kingdom
Background

Albuminuria is an independent risk factor for the progression to end-stage kidney failure and premature mortality. It is well-established that podocyte damage is a major cause of albuminuria, yet the pathways involved are incompletely understood. In this study, we analysed the transcriptomes of insulin-sensitive and insulin-resistant podocytes to identify molecules regulated in podocyte damage and novel pathways regulating albuminuria in diabetes. This revealed that Neuropeptide Y (Npy) was highly downregulated in insulin-resistant podocytes. While NPY is implicated in many conditions including obesity, diabetes and insulin resistance, a role for NPY in albuminuric kidney disease has not been described.

Methods

Gene expression was analysed in vitro in conditionally-immortalised podocytes using RNA sequencing and focused qPCR arrays, and in vivo in the Pima type-2 diabetic nephropathy cohort and the “nephroseq” database. The effect of reduced Npy expression on albuminuria was analysed in streptozotocin (STZ)-induced diabetic nephropathy and Adriamycin-nephropathy models, using wild-type and NPY-deficient (NPY-/-) mice. Conditionally-immortalized human and mouse podocytes were studied in vitro to determine the effects of NPY signalling. The effects of pharmacological NPY2R inhibition were investigated in vitro and in vivo, using BIIE0246.

Results

Transcriptome analysis demonstrated that Npy was significantly down-regulated in insulin-resistant vs insulin-sensitive mouse podocytes. Human diabetic nephropathy (DN) patients also had reduced glomerular NPY expression in both early- and late-stage DN. However, NPY-/- mice had reduced levels of albuminuria and podocyte injury in both diabetic and non-diabetic kidney disease models. Furthermore, both human and mouse podocytes responded to NPY stimulation, via activation of PI3K and ERK MAPK signalling cascades, as well as the calcium-dependent activation of NFAT; responses which were mediated through NPY2 receptor (NPY2R) activity. The pharmacological inhibition of NPY2R in vivo significantly reduced albuminuria in adriamycin-treated mice.

Conclusion

Our findings reveal a novel role for the NPY system in the glomerulus and suggest that manipulating NPY-NPY2R signalling in albuminuric kidney disease may be therapeutically beneficial.

Funding

  • NIDDK Support