Extracellular signals and intracellular pathways in diabetic nephropathy

The pathogenesis of diabetic nephropathy (DN) includes genetic, haemodynamic and metabolic factors and oxidative stress as well as renal hypertrophy. Among them, hyperglycaemia is necessary, but not sufficient, for the development of DN. The toxicity of hyperglycaemia results from glucose overutilization and multiple secondary effects. Renal cells respond to extracellular signals [high glucose, glycated proteins, mechanical strain, cytokines/growth factors, especially angiotensin II (AII) and transforming growth factor-beta (TGF-beta)] by way of cell-surface receptors and activating or inhibiting intracellular pathways. These pathways form a complex network with extensive interactions. Intracellular pathways relevant in DN are polyol, protein kinase C (PKC, especially the PKC beta isoform), reactive oxygen species (ROS, associated with many pathways), nitric oxide (NO; through increased expression of endothelial constitutive NO synthase), mitogen-activated protein kinase (MAPK) cascade (extracellular signal-regulated kinase and p38 MAPK may act as glucose transducers), calcium, Janus kinase (JAK)/signal transducers and activators of transcription (STAT), NF-kappaB (an inflammatory transcription factor), Smads (transcription factors activated by TGF-beta superfamily), cell cycle regulatory proteins (retinoblastoma protein phosphorylation; cdc2 kinase; p16(INK4), p21(Cip1) and p27(kip1) cyclin-dependent kinase inhibitors), AP-1 (a heterodimer of Fos and Jun transcription factors) and transcriptional co-activators (e.g. CBP/p300, which binds to NF-kappaB, STATs, Smads and AP-1, thereby enabling the interactions among these signals). The therapeutic effects of AII inhibition are mediated by haemodynamic and non-haemodynamic factors. In fact, because AII induces TGF-beta and many DN-related intracellular pathways (e.g. PKC, ROS, MAPK, JAK/STAT, NF-kappaB and AP-1), many of the non-haemodynamic effects of AII inhibition may be mediated by inhibiting these pathways. While some extracellular signals (mechanical strain, hyperglycaemia, AII and TGF-beta) have fulfilled Koch's postulates, none of the intracellular pathways have. However, many inhibitors of these intracellular pathways are being actively researched. These inhibitors may be useful in future therapy for DN.