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A New Insight into Molecular Function of Smads Signalings in Diabetic Nephropathy

Hiroyuki Ono, Hideharu Abe and Toshio Doi

Diabetic Nephropathy (DN) is the leading cause of end-stage renal failure and is associated with increased morbidity and mortality compared with other causes of renal diseases. Therefore, it is important to elucidate the pathogenesis of DN and establish effective therapies for its treatment. Morphologically, DN is characterized by mesangial matrix expansion caused by the excessive deposition of extracellular matrix proteins such as type IV collagen. Prolonged exposure to hyperglycemia induces Advanced Glycation End Products (AGEs). AGE/RAGE (receptor for AGE) axis induces Bone Morphogenetic Proteins 4 (BMP4) and transforming growth factor-β (TGF-β). Both BMP4/Smad1 and TGF-β/Smad3 signaling pathways are involved in the progression of DN. In particular, Smad1 is the key signaling molecule that is directly involved in the initiation and progression of glomerulosclerosis in DN. BMP4 induces Smad1 and phosphorylation of Smad1 C-terminal domain, its interaction with Smad4, and its translocation into the nucleus, where it regulates the transcription of Col4. However, no study has elucidated the mechanisms underlying the significance of Smad1 linker domain (pSmad1L) in DN. Moreover, the precise role of Smad3 signaling pathway under diabetic conditions is not completely understood, including the correlation between Smad1 and Smad3 signaling. This review article shows that pSmad1L is very important for attenuating DN, and that a new molecular interplay between Smad1 and Smad3 signaling under a diabetic condition might facilitate novel therapeutic agents.