A role for NPY-NPY2R signaling in albuminuric kidney disease

Lay, A C and Barrington, A F and Hurcombe, J A and Ramnath, R D and Graham, M and Lewis, P A and Wilson, M C and Heesom, K J and Butler, M J and Perrett, R M and Neal, C R and Herbert, E and Mountjoy, E and Atan, D and Nair, V and Ju, W and Nelson, R G and Kretzler, M and Satchell, S C and McArdle, C A and Welsh, G I and Coward, R J M (2020) A role for NPY-NPY2R signaling in albuminuric kidney disease. Proceedings of the National Academy of Sciences, 117 (27). pp. 15862-15873. ISSN 0027-8424

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Official URL: https://doi.org/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. Chronic kidney disease (CKD) is a major global healthcare concern, affecting over 10% of the general population, and frequently occurs secondary to other systemic disorders including diabetes, obesity, hypertension, and the metabolic syndrome. A common early hallmark of CKD is albuminuria, which not only reflects damage to the glomerular filtration barrier (GFB) in the kidney but also is an important independent risk factor for the progression to end-stage renal failure and cardiovascular disease (1⇓–3). Thus, strategies to prevent albuminuria have important therapeutic potential, particularly in the early stages of CKD progression. Podocytes are highly specialized epithelial cells of the glomerulus, lining the urinary side of the filtration barrier. Owing to their complex, dynamic structures and their ability to secrete (and adapt to) a number of growth factors, these cells have a central role in filtration barrier maintenance (4). As such, podocyte damage is a key driver of albuminuria and glomerular disease in numerous settings and occurs early in the pathogenesis of many albuminuric conditions (5⇓⇓⇓–9). While it is well-established that podocyte damage is a major cause of albuminuria (8), the pathways and molecules involved in podocyte injury are incompletely understood. We (10, 11) and others (12, 13) have highlighted the importance of podocyte insulin responses in maintaining glomerular function, and it is now evident that circulating factors associated with common systemic disorders, including diabetes, obesity, and the metabolic syndrome, can directly induce podocyte insulin resistance (14⇓⇓–17) and associated damage (15, 18). In this study, we analyzed the transcriptomes of insulin-sensitive and insulin-resistant podocytes with the aim of identifying molecules that are differentially regulated in podocyte damage, which may play a role in albuminuric kidney disease. This unbiased transcriptome analysis revealed that Neuropeptide Y (Npy) was the most highly down-regulated transcript in insulin-resistant vs. insulin-sensitive podocytes. Analysis of patient cohorts also revealed a significant reduction in glomerular NPY expression in both early and late-stage diabetic nephropathy (DN), as well as in several other human albuminuric conditions. This contrasts with the increased plasma and urinary levels of NPY that are observed in diabetes and CKD (19⇓⇓–22). This prompted us to further investigate the potential role of NPY (and NPY signaling) in the podocyte and glomerulus.

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