New developments concerning the proximal tubule in diabetic nephropathy: in vitro models and mechanisms

The incidence of Type 2 diabetes is increasing rapidly worldwide, and understanding the mechanisms of its complications including diabetic nephropathy (DN) is important in the discovery of early biomarkers, understanding the causative mechanisms of its complications and identifying therapeutic targets. DN is characterized by glomerulosclerosis, tubulointerstitial fibrosis and tubular atrophy. The tubular component of the disease is important in progression of disease. In vitro models are a valuable alternative to animal studies and an effective way to explore mechanisms of human disease. Several proximal tubular cell lines have been used in studying mechanisms of DN. Key extracellular conditions that contribute to damage to the proximal tubule in DN include hyperglycaemia, proteinuria, and hypoxia and inflammation. According to current knowledge, these exert their effects through changes in transforming growth factor beta signalling, the renin-angiotensin system, dysregulation of pathways such as the polyol pathway, hexosamine pathway and protein kinase C pathway and through formation of advanced glycation end products. Studies in cell culture models have been instrumental in the delineation of these processes. However, all of the existing cell culture models have limitations including dedifferentiation. To bring research forward along with technological advances, such as major advances in 'omics' methodologies, a more suitable model is necessary. The RPTEC/TERT1 cell line is a promising alternative to previous proximal tubular epithelial cell lines due to features that resemble the cell type in vivo, such as its epithelial characteristics, maintenance of functional capabilities, glucose handling, expression of the primary cilium and transport activity including albumin. This cell line will facilitate identification of mechanisms of DN with potential to identify new therapeutic targets.