A new pair of SOCS for diabetic nephropathy.

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 homoor 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 the early part of the past decade several investigators, led by Marrero’s group, documented that exposure to elevated glucose concentrations results in activation of JAK2/STAT signaling in a variety of cell types as well as in the renal cortex of rodents with early diabetic nephropathy.1–5 Induction of TGFand fibronectin expression from JAK2/ STAT signaling is abrogated by JAK2 inhibition.2,5 These studies suggested JAK2 activation associates with the development of diabetic complications. Experiments using a streptozotocin-induced diabetic rat model found that both increased systolic BP6 and albuminuria7 were prevented by treatment with the JAK2 inhibitor AG490, lending further credence to the idea that JAK2 activation plays an important role in diabetic nephropathy. Until recently, it has been uncertain whether changes in JAK2/STAT activation occur in human diabetic nephropathy. In 2009, Berthier et al.8 documented enhanced expression of a large number of JAK/STAT mRNAs and JAK2 protein in glomeruli and the tubulointerstitium from humans with both early and progressive diabetic nephropathy JAK2 mRNA levels inversely correlated with estimated GFR in these patients. Moreover, increased JAK2 expression alone enhanced JAK2 activity in cultured glomerular mesangial cells. Interestingly, JAK/STAT expression is not enhanced in glomerular or tubulointerstitial tissues from two of the best current murine models of diabetic nephropathy. Humans with diabetic nephropathy seem to have enhanced JAK/STAT activation both by exposure to high glucose and by enhanced expression of genes encoding JAK/STAT. Thus, the lack of chronically enhanced expression of JAK/STAT genes in mouse models could be one explanation for why rodent models only mimic early human nephropathy and fail to develop progressive disease. In this issue of JASN, Ortiz-Munoz et al.9 provide a new chapter in the JAK/STAT story by demonstrating that downstream transcriptional targets of this pathway, suppressors of cytokine signaling (SOCS) genes, are activated in rodents with diabetic nephropathy. SOCS proteins bind and interfere with initiating JAK proteins in a negative-feedback manner.10 Some SOCS proteins also bind to receptor phosphotyrosine residues on the cytokine receptors themselves and further inhibit signaling by competing with STAT molecules for recruitment to the receptor/JAK/STAT complex. Thus, SOCS proteins serve to suppress the JAK/STAT signaling that triggers their expression. This presumably protective feedback response could be critical in a chronic disease such as diabetic nephropathy, which is accompanied by enhanced JAK/STAT expression and activation that presumably lasts for years, if not decades. In the streptozotocin-induced diabetic rat model, OrtizMunoz et al.9 demonstrate a robust and seemingly chronic increase in levels of SOCS1 and SOCS3. Both of these SOCS proteins inhibit JAK2 signaling. Increased SOCS1 and SOCS3 expression is also observed in humans with progressive diabetic nephropathy when compared with patients with minimal-change disease.9 It seems the highest expression of SOCS proteins is in proximal tubular cells as well as in some glomerular cells, which is a similar distribution to that of JAK2 in human diabetic nephropathy.8 Ortiz-Munoz et al.9 also adPublished online ahead of print. Publication date available at www.jasn.org.