oa Editorial [Hot topic: Proteinuria in Diabetes: an Endocrine Disease? (Guest Editor: Alessia Fornoni and Oliver Lenz)]

Diabetic nephropathy (DN) affects both patient with type 1 and type 2 diabetes and represents a major burden to public health cost [1]. Tight glycemic and blood pressure control can dramatically slow the progression of the disease, particularly when diagnosed and intervened upon in the early stages [2]. However, a definitive cure remains to be found, and a large number of patients progress towards end-stage renal disease despite the currently employed measures. Finding a cure is hindered by the multiplicity of pathogenetic pathways, some already identified and others waiting to be discovered. An early and key event in the development of DN is the loss of podocytes from the kidney glomerulus. Podocytes are highly specialized cells that form foot processes and the glomerular slit diaphragm (SD) [3], a complex cellular organization that prevents the development of proteinuria [4]. The podocyte SD is composed of an ever increasing number of molecules that are finely interconnected and functionally dependent on the integrity of the actin cytoskeleton [5]. Most of the molecules that compose the SD have initially been thought to be primarily structural molecules, but it has become clear that each of these can initiate a cascade of signaling events that affect podocyte function [6]. A major research focus has been placed on how locally initiated events lead to podocyte damage in diabetes. In addition, the evidence that podocytes express receptors for many circulating hormones has suggested that a more complex cross talk between the kidney filtration barrier and other organs may occur in health and disease. This hot topic issue of CDR reviews the clinical and experimental evidence that hormonal derangements that characterize diabetes may be associated with the severity of proteinuria, which may be caused by a change in the ability of podocytes to respond to hormones such as insulin, sex hormones, growth hormone, adipokines, aldosterone, prorenin, angiotensin II, and Vitamin D. We selected hormones for which both podocyte receptor expression and clinical relevance have been suggested by prior studies. We excluded other hormones/parahormones that are most likely additional important modulator of podocytes function, such as free fatty acids (FFA), lipoproteins, adrenocorticotropic hormone (ACTH), growth hormone releasing hormone (GHRH), and thyroid hormones as we believe more studies are needed to support their specific function in DN. Campbell et al. review the role of angiotensin II as a modulator of proteinuria and podocyte malfunction in diabetes. In particular, the mechanisms by which local activation of the renin angiotensin system (RAS) in podocytes may lead to altered expression and distribution of slit diaphragm components are discussed. Nagase highlights the intriguing possibility that the anti-proteinuric effect of mineralocorticoid receptor (MR) antagonists may be linked to modulation of MR signaling in podocytes, which could be mediated by aldosterone binding to the MR receptor or through ligand-independent activation of MR by Rac 1, a small GTPase implicated in podocyte function. Ichihara et al. appraise the role of prorenin in the pathogenesis of DN and podocyte malfunction in diabetes and examine the experimental evidence that a decoy peptide that competitively inhibits the binding of prorenin to the (pro)renin receptor protects from the development of albuminuria in DN. This finding is highly relevant clinically, particularly in light of the recent evidence that podocytes express prorenin receptor and that prorenin receptor expression is modulated in the hyperfiltering kidney. Both local angiotensin II dependent and independent mechanisms of action are discussed. Given that insulin resistance correlates with the development of albuminuria in both diabetic and non diabetic patients [7], Coward et al. assess the clinical and experimental evidence that insulin resistance and hyperinsulinemia may play a pathogenetic role in the development of podocytopathy and proteinuria in DN. Insights gained may lead to the preferential utilization of selective hypoglycemic agents when trying to achieve superior renoprotection for an equal hemoglobin A1C target. The subsequent articles focus on hormones targeting nuclear receptors, namely estrogens and Vitamin D. Doublier et al. discuss the role of estrogens in the progression of diabetes-induced kidney injury and the effects of estrogens in podocyte signaling and survival. It is interesting to note that an intracrine mechanism of estrogen action in the diabetic kidney may occur: this recent finding adds complexity to how sex hormones and aromatase activity influence the development of DN [8]. Dr. Li discusses the intriguing possibility that the antiproteinuric effect observed in vitamin D treated patients and experimental animals might be related to a direct effect of Vitamin D on important signaling cascades in podocytes, such as the RAS and Wnt/b-catenin pathways. This review sheds light on novel functions of vitamin D that are beyond the traditional regulation of calcium and phosphorus metabolism. In order to underline the importance of a cross talk between different organs affected by diabetes, Mathew et al. review the role of adipokines in the development of the kidney disease observed in diabetes and obesity, with a focus on podocyte biology. The clinical evidence correlating serum levels of adipokines and macrovascular and microvascular complications is also addressed....