A New Pair of SOCS for Diabetic Nephropathy

Abstract

Over the years, disorders in a variety of signaling pathways have been implicated in the evolution of diabetic nephropathy. Despite these efforts, there remains no consensus about the signaling abnormalities that are fundamental to renal progression. One example of disordered signaling that has received increasing attention, however, is that of enhanced activation of janus kinase/signal transducers and activators of transcription (JAK/STAT) proteins in both glomerular and tubulointerstitial cells in humans with diabetic nephropathy and in some animal models. JAK/STAT members are protein pairs that rapidly and efficiently transduce signaling activated by the binding of cytokines such as IL-6 and G-protein–coupled receptor agonists such as angiotensin II to their cognate receptors. Upon cytokine receptor activation, the associated JAK protein, a tyrosine kinase, phosphorylates residues in SH2 domains on the cytoplasmic domain of the receptor. This initiates recruitment of the STAT partner, which is then phosphorylated by the JAK protein. STAT proteins then homo- or heterodimerize and translocate into the nucleus, where they bind to promoter regions of many target genes to transactivate them. Although there are four members in the mammalian JAK family, the one best studied in renal and vascular tissues is JAK2. Starting in …