2. Academic Validation
  3. A role for NPY-NPY2R signaling in albuminuric kidney disease

A role for NPY-NPY2R signaling in albuminuric kidney disease

  • Proc Natl Acad Sci U S A. 2020 Jul 7;117(27):15862-15873. doi: 10.1073/pnas.2004651117.
Abigail C Lay 1,  A Fern Barrington 1,  Jenny A Hurcombe 1,  Raina D Ramnath 1,  Mark Graham 1,  Philip A Lewis 2,  Marieangela C Wilson 2,  Kate J Heesom 2,  Matthew J Butler 1,  Rebecca M Perrett 3,  Chris R Neal 1,  Eleanor Herbert 4 5,  Edward Mountjoy 6,  Denize Atan 7,  Viji Nair 8 9,  Wenjun Ju 8 9,  Robert G Nelson 10,  Matthias Kretzler 8 9,  Simon C Satchell 1,  Craig A McArdle 3,  Gavin I Welsh 1,  Richard J M Coward 11
Affiliations

Affiliations

  • 1 Bristol Renal, Bristol Medical School, University of Bristol, Bristol BS1 3NY, United Kingdom.
  • 2 Proteomics Facility, University of Bristol, Bristol BS8 1TD, United Kingdom.
  • 3 Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS1 3NY, United Kingdom.
  • 4 Department of Pathobiology, The Royal Veterinary College, University of London, North Mymms AL9 7TA, United Kingdom.
  • 5 Department of Population Sciences, The Royal Veterinary College, University of London, North Mymms AL9 7TA, United Kingdom.
  • 6 Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol BS8 2BN, United Kingdom.
  • 7 Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1TD, United Kingdom.
  • 8 Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
  • 9 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109.
  • 10 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ 85016.
  • 11 Bristol Renal, Bristol Medical School, University of Bristol, Bristol BS1 3NY, United Kingdom; [email protected].
PMID: 32561647 DOI: 10.1073/pnas.2004651117
Abstract

Albuminuria is an independent risk factor for the progression to end-stage kidney failure, cardiovascular morbidity, and premature death. As such, discovering signaling pathways that modulate albuminuria is desirable. Here, we studied the transcriptomes of podocytes, key cells in the prevention of albuminuria, under diabetic conditions. We found that Neuropeptide Y (NPY) was significantly down-regulated in insulin-resistant vs. insulin-sensitive mouse podocytes and in human glomeruli of patients with early and late-stage diabetic nephropathy, as well as other nondiabetic glomerular diseases. This contrasts with the increased plasma and urinary levels of NPY that are observed in such conditions. Studying NPY-knockout mice, we found that NPY deficiency in vivo surprisingly reduced the level of albuminuria and podocyte injury in models of both diabetic and nondiabetic kidney disease. In vitro, podocyte NPY signaling occurred via the NPY2 receptor (NPY2R), stimulating PI3K, MAPK, and NFAT activation. Additional unbiased proteomic analysis revealed that glomerular NPY-NPY2R signaling predicted nephrotoxicity, modulated RNA processing, and inhibited cell migration. Furthermore, pharmacologically inhibiting the NPY2R in vivo significantly reduced albuminuria in adriamycin-treated glomerulosclerotic mice. Our findings suggest a pathogenic role of excessive NPY-NPY2R signaling in the glomerulus and that inhibiting NPY-NPY2R signaling in albuminuric kidney disease has therapeutic potential.

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