Angiotensin II Signaling in Diabetic Nephropathy

DESCRIPTION (provided by applicant): Our group has recently found that high glucose (HG) augmented the angiotensin II (Ang II)-induce growth of glomerular mesangial cells (GMC) by increasing signal transduction through the JAK (janus kinase)/STAT (signal transducers and activation of transcription) pathway. Our general hypothesis is that the Ang II-induced JAK/STAT pathway plays a central role in abnormal GMC growth in type I diabetes mellitus. Therefore, the overall goal of this proposal is to define the molecular mechanisms by which HG enhances the Ang II-induce activation of the JAK/STAT pathway in an effort to elucidate the processes of abnormal GMC growth that occur during diabetes. We plan to use an integrated approach using molecular and biochemical techniques in cultured GMC along with in vivo studies in STZ-induced diabetic rats in order to address the following specific aims: 1. To test the hypothesis that HG augments the Ang II-induced JAK/STAT pathway in GMC through reactive oxygen species generated via the polyol pathway. 2. To test the hypothesis that reactive oxygen species generated by HG augment the Ang II-induced JAK/STAT pathway in GMC by modulating the cytosolic tyrosine phosphatases SHP-1 and SHP-2. 3. To test the hypothesis that HG augments the Ang II-induced growth responses in GMC via the JAK/STAT pathway. 4. To test the hypothesis that the activation of JAK2 and the different STAT proteins in the glomeruli of STZ-induced diabetic rats is mediated by 1) AT1 receptor activation, 2) activation of the polyol pathway, and 3) overproduction of reactive oxygen species. 5. To test the hypothesis that JAK2 plays a role in TGF-beta production and extracellular matrix accumulation (i.e., fibronectin and collagen IV) in glomeruli of STZ-induced diabetic rats. We believe that it is important to characterize the molecular mechanisms responsible for abnormal cell growth in diabetes with the hope that prevention of such growth will delay the onset, retard the progression, or even prevent renal disease.