A role for NPY-NPY2R signaling in albuminuric kidney disease.

Proceedings of the National Academy of Sciences of the United States of America 2020 Jul 07

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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. Copyright © 2020 the Author(s). Published by PNAS.

Citation

Abigail C Lay, A Fern Barrington, Jenny A Hurcombe, Raina D Ramnath, Mark Graham, Philip A Lewis, Marieangela C Wilson, Kate J Heesom, Matthew J Butler, Rebecca M Perrett, Chris R Neal, Eleanor Herbert, Edward Mountjoy, Denize Atan, Viji Nair, Wenjun Ju, Robert G Nelson, Matthias Kretzler, Simon C Satchell, Craig A McArdle, Gavin I Welsh, Richard J M Coward. A role for NPY-NPY2R signaling in albuminuric kidney disease. Proceedings of the National Academy of Sciences of the United States of America. 2020 Jul 07;117(27):15862-15873