? Valid murine models of diabetic nephropathy (DN) should replicate the molecular changes and not simply the pathological alterations of patients with DN. Thus, our general hypothesis for development and testing of murine models of diabetic nephropathy is that Current murine models fail to show human-like DN because they fail to replicate glomerular and tubulointerstital gene expression changes that occur in humans with progressive DN. Replication of the critical transcriptomic profiles of patients with progressive DN should induce progressive DN in mice. Our use of data in human DN generated by the European Renal cDNA Bank (ERCB) will be critical in testing and validating the mouse models of the Animal Models of Diabetic Complications Consortium. We have performed initial transcriptomic analyses of humans with DN using the ERCB to identify pathways which are reliably altered in humans but not in murine models. One pathway that is consistently altered in glomeruli and tubulointerstium in diabetes in humans, but not in mice, is the JAK/STAT pathway. Expression of all JAK members was increased when confirmed with real time PCR analysis. We have focused on JAK2 given its key role in mediating responses implicated in DN. Moreover, JAK2 is activated by reactive oxygen species and interacts with PPAR( signaling, both of which are implicated in DN. For our 2 novel models, we propose podocyte and proximal tubular-specific Jak2 transgenic db/m C57BLKS mice. For these and other models in the Consortium we propose to: ? 1. Determine whether transcriptional changes in humans are reproduced in the glomerular and tubulointersitial compartments of the Jak2//db/db BLKS models, and other AMDCC models; ? 2. Determine if all the pathologic and pathophysiologic features of human DN are replicated in the Jak2//db/db BLKS models; ? 3. Determine if JAK2/3 inhibitors prevent development of DN in the Jak2 transgenic models and other good candidate models that replicate human transcriptomic changes; ? 4. Determine if ROS production drives JAK2 expression in glomerular and/or tubulointerstitial compartments and enhances downstream JAK2 signaling and whether JAK2 expression promotes ROS; ? 5. Determine if PPAR( agonists prevent J.ak2 downstream effects in glomerular and/or tubulointerstitial compartments. ? This research is directly relevant to the study and prevention of diabetic kidney disease, the major cause of kidney failure in the U.S. By creating and understanding a mouse model that develops human-like diabetic kidney disease, we can then move rapidly to tests of strategies to prevent and cure this disease. ? ?
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