? 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK076139-02
Application #
7288258
Study Section
Special Emphasis Panel (ZDK1-GRB-4 (M1))
Program Officer
Ketchum, Christian J
Project Start
2006-09-30
Project End
2011-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$290,561
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhang, Hongyu; Nair, Viji; Saha, Jharna et al. (2017) Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice. Kidney Int 92:909-921
Hodgin, Jeffrey B; Nair, Viji; Zhang, Hongyu et al. (2013) Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli. Diabetes 62:299-308
Buller, Carolyn L; Heilig, Charles W; Brosius 3rd, Frank C (2011) GLUT1 enhances mTOR activity independently of TSC2 and AMPK. Am J Physiol Renal Physiol 301:F588-96
Zhang, Hongyu; Schin, MaryLee; Saha, Jharna et al. (2010) Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice. Am J Physiol Renal Physiol 299:F91-8
Brosius, Frank C; Khoury, Charbel C; Buller, Carolyn L et al. (2010) Abnormalities in signaling pathways in diabetic nephropathy. Expert Rev Endocrinol Metab 5:51-64
Ju, Wenjun; Brosius 3rd, Frank C (2010) Understanding kidney disease: toward the integration of regulatory networks across species. Semin Nephrol 30:512-9
Brosius 3rd, Frank C; Alpers, Charles E; Bottinger, Erwin P et al. (2009) Mouse models of diabetic nephropathy. J Am Soc Nephrol 20:2503-12
Berthier, Celine C; Zhang, Hongyu; Schin, MaryLee et al. (2009) Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes 58:469-77
Zhang, Hongyu; Saha, Jharna; Byun, Jaeman et al. (2008) Rosiglitazone reduces renal and plasma markers of oxidative injury and reverses urinary metabolite abnormalities in the amelioration of diabetic nephropathy. Am J Physiol Renal Physiol 295:F1071-81
Wiggin, Timothy D; Kretzler, Matthias; Pennathur, Subramaniam et al. (2008) Rosiglitazone treatment reduces diabetic neuropathy in streptozotocin-treated DBA/2J mice. Endocrinology 149:4928-37

Showing the most recent 10 out of 12 publications