A role for NPY-NPY2R signaling in albuminuric kidney disease
| Autor: | Robert G. Nelson, Matthias Kretzler, Abigail C Lay, Viji Nair, Christopher R. Neal, Gavin I. Welsh, Jenny A Hurcombe, Marieangela C. Wilson, Raina D. Ramnath, Philip A. Lewis, A Fern Barrington, Kate J. Heesom, Wenjun Ju, Matthew J. Butler, Craig A. McArdle, Mark A. Graham, Denize Atan, Rebecca M. Perrett, Edward Mountjoy, Richard J M Coward, Simon C. Satchell, Eleanor Herbert |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Proteomics medicine.medical_specialty Medical Sciences Bristol Heart Institute Kidney Glomerulus Down-Regulation urologic and male genital diseases Arginine Podocyte Diabetes Mellitus Experimental Diabetic nephropathy Mice Diabetes mellitus Internal medicine mental disorders medicine Albuminuria Animals Humans Insulin Diabetic Nephropathies Neuropeptide Y PI3K/AKT/mTOR pathway Mice Knockout Kidney Mice Inbred BALB C Multidisciplinary business.industry urogenital system Podocytes NFAT Biological Sciences Benzazepines medicine.disease humanities Receptors Neuropeptide Y Disease Models Animal medicine.anatomical_structure Endocrinology Doxorubicin Kidney Diseases medicine.symptom business Kidney disease Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Lay, A C, Barrington, A F, Hurcombe, J A, Ramnath, R D, Graham, M, Lewis, P A, Wilson, M C, Heesom, K J, Butler, M J, Perrett, R M, Neal, C R, Herbert, E, Mountjoy, E, Atan, D, Nair, V, Ju, W, Nelson, R G, Kretzler, M, Satchell, S C, McArdle, C A, Welsh, G I & Coward, R J M 2020, ' A role for NPY-NPY2R signaling in albuminuric kidney disease ', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 27, 202004651, pp. 15862-15873 . https://doi.org/10.1073/pnas.2004651117 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Neuropeptide Y (NPY) is implicated in many pathological conditions including obesity, diabetes, and insulin resistance. However, a pathogenic role of NPY in kidney disease has not been described. We found that NPY is produced by the podocyte in the glomerulus, and this production decreases in renal disease, in contrast to an increase in circulating NPY levels. In the glomerulus, NPY signals via the NPY receptor 2 (NPY2R) and modulates PI3K, MAPK, and NFAT signaling, along with RNA processing and cell migration and, if prolonged, predicted nephrotoxicity. The pharmacological inhibition of NPY-NPY2R signaling also protected against albuminuria and kidney disease in a mouse model of glomerulosclerosis, suggesting that inhibiting this pathway may be therapeutically beneficial in the prevention of kidney disease. 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. |
| Databáze: | OpenAIRE |
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