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A role for NPY-NPY2R signaling in albuminuric kidney disease

Lay, Abigail C. ; Barrington, A. Fern ; Hurcombe, Jenny A. ; Ramnath, Raina D. ; Graham, Mark ; Lewis, Philip A. ; Wilson, Marieangela C. ; Heesom, Kate J. ; Butler, Matthew J. ; Perrett, Rebecca M. ; Neal, Chris R. ; Herbert, Eleanor ; Mountjoy, Edward ; Atan, Denize ; Nair, Viji ; Ju, Wenjun ; Nelson, Robert G. ; Kretzler, Matthias ; Satchell, Simon C. ; McArdle, Craig A. ; Welsh, Gavin I. ; Coward, Richard J. M.

Proceedings of the National Academy of Sciences - PNAS, 2020-07, Vol.117 (27), p.15862-15873 [Periódico revisado por pares]

United States: National Academy of Sciences

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Título:
A role for NPY-NPY2R signaling in albuminuric kidney disease
Autor: Lay, Abigail C. ; Barrington, A. Fern ; Hurcombe, Jenny A. ; Ramnath, Raina D. ; Graham, Mark ; Lewis, Philip A. ; Wilson, Marieangela C. ; Heesom, Kate J. ; Butler, Matthew J. ; Perrett, Rebecca M. ; Neal, Chris R. ; Herbert, Eleanor ; Mountjoy, Edward ; Atan, Denize ; Nair, Viji ; Ju, Wenjun ; Nelson, Robert G. ; Kretzler, Matthias ; Satchell, Simon C. ; McArdle, Craig A. ; Welsh, Gavin I. ; Coward, Richard J. M.
Assuntos: 1-Phosphatidylinositol 3-kinase ; Albuminuria - metabolism ; Animals ; Arginine - analogs & derivatives ; Arginine - pharmacology ; Benzazepines - pharmacology ; Biological Sciences ; Cell adhesion & migration ; Cell migration ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - metabolism ; Diabetic Nephropathies ; Disease Models, Animal ; Down-Regulation ; Doxorubicin - pharmacology ; End-stage renal disease ; Glomerulus ; Humans ; Injury prevention ; Insulin ; Insulin - metabolism ; Kidney diseases ; Kidney Diseases - metabolism ; Kidney Diseases - pathology ; Kidney Glomerulus - drug effects ; Kidney Glomerulus - pathology ; Kidneys ; Male ; MAP kinase ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Morbidity ; Nephropathy ; Neuropeptide Y ; Neuropeptide Y - metabolism ; Neuropeptide Y - pharmacology ; Neuropeptide Y - urine ; NF-AT protein ; Podocytes - metabolism ; Proteomics ; Receptors, Neuropeptide Y - drug effects ; Receptors, Neuropeptide Y - metabolism ; Renal failure ; Risk analysis ; Risk factors ; RNA processing ; Rodents ; Signal Transduction - drug effects ; Signal Transduction - physiology ; Signaling
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2020-07, Vol.117 (27), p.15862-15873
Notas: Edited by Martin R. Pollak, Beth Israel Deaconess Medical Center, Brookline, MA, and approved May 18, 2020 (received for review March 18, 2020)
Author contributions: A.C.L., G.I.W., and R.J.M.C. designed research; A.C.L., A.F.B., J.A.H., R.D.R., M.G., P.A.L., M.C.W., K.J.H., M.J.B., R.M.P., C.R.N., E.H., D.A., V.N., W.J., R.G.N., M.K., S.C.S., and C.A.M. performed research; M.G., P.A.L., M.C.W., K.J.H., C.R.N., E.H., E.M., D.A., V.N., W.J., R.G.N., and M.K. analyzed data; A.C.L. and R.J.M.C. wrote the manuscript and all authors reviewed, commented, and approved.
Descrição: 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.
Editor: United States: National Academy of Sciences
Idioma: Inglês;Chinês

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A role for NPY-NPY2R signaling in albuminuric kidney disease

United States: National Academy of Sciences

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