Diabetic nephropathy and transcription factors.

Abstract

Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus (DM) and is an important cause of increased morbidity and mortality in patients with DM. Multiple factors, including an interaction between hyperglycemia-induced metabolic and hemodynamic changes [1] and genetic predisposition [2], have been shown to contribute to the development of DN. Currently, the mainstay of therapy for DN is improving glucose control and lowering systemic blood pressure with renin– angiotensin system inhibitors. However, despite those therapeutic regimens, the prevalence of DN has been increasing, and novel strategies are urgently needed. DN is primarily glomerular injury, which is histologically defined as glomerular basement membrane thickening and excess accumulation of mesangial extracellular matrix proteins, although tubular injury or tubulointerstitial fibrosis is also a prominent component of the disease [3, 4]. Hyperglycemia present in the diabetic milieu induces a number of pathways, such as the activation of protein kinase C [5], accumulation of inflammatory mediators or growth factors [6] and advanced glycation end products (AGEs) [7], and the generation of reactive oxygen species (ROS) [8], in a variety of cell types in the kidney. Nevertheless, knowledge of the mechanism of gene regulation that elicits the biological response to glucose-mediated biochemical derangements is lacking. Recently, investigations in mesangial cells and in glomerular cells in vitro and in vivo have highlighted transcription factors that participate in the regulation of gene expression in diabetic circumstances. For example, the Smad family of proteins, including Smad1 and Smad3, are activated in response to stimuli such as transforming growth factor beta (TGF-b) and AGEs to upregulate the production of extracellular matrix proteins by mesangial cells at the transcriptional level [9– 11]. The transcription factor NF-jB is activated by cellular stimulation with ROS or cytokines induced by high glucose, and contributes to microinflammation of glomeruli [12]. STAT1 and STAT3, which are activated by high glucose or by increased angiotensin II in glomerular mesangial cells, are implicated in the production of extracellular matrix proteins and control of cellular growth [13]. Diverse cellular signaling pathways may converge on a transcription factor, and transcriptional dysregulation in the diabetic kidney can occur at multiple levels, including alterations in upstream signals or the transcription factor itself. In this respect, transcription factors are the final effector proteins at the site of gene regulation to mediate the cellular responses to pathogenic factors in diabetes. Therefore, transcription factors may represent attractive therapeutic targets that could circumvent many of the problems with signal redundancy and crosstalk that are often experienced in therapies targeting upstream of the cellular signals. Despite the apparent progress in this field of research, difficulties in developing strategies for ‘‘drugging’’ transcription factors have been encountered. Some transcription factors, such as estrogen receptor in endocrine therapy for cancers [14] and glucocorticoid receptor in anti-inflammation or immunosuppression therapy [15], are directly regulated by, e.g., synthetic steroid ligands. For the other transcription factors, however, indirect targeting designs are available: decoy oligonucleotides to disrupt & Yuichi Makino makino@asahikawa-med.ac.jp