Nrf2 ameliorates diabetic nephropathy progression by transcriptional repression of TGFβ1 through interactions with c-Jun and SP1.
Growth factors play an important role in the development of functional and structural changes associated with diabetic nephropathy. Although it has been known for years that these factors are important for early renal hypertrophy and subsequent development of glomerulosclerosis and tubulointerstitial fibrosis, the exact molecular mechanism of many of these factors has only recently been more elucidated. Furthermore, growth factors also link the metabolic theory of diabetic complications with renal hemodynamic changes in diabetic nephropathy because some growth factors could directly influence glomerular hemodynamics and tubular transport in diabetic nephropathy. The high glucose environment with stimulated cellular uptake of glucose and accelerated nonenzymatic reactions resulting in Amadori-modified proteins and the later-developing advanced glycation end products are the main stimulators for intrarenal induction of growth factors. Intracellular generation of reactive species is an important signal intermediate in these stimulated expressions of growth factors. Taking into consideration the pivotal role of growth factors in the development of diabetic nephropathy, a therapeutic strategy to antagonize growth factor effects appears to be straightforward. However, the pleiotropic function of many of these factors and their physiologic role in normal renal homeostasis may make this approach difficult.