- Diabetic neuropathy progressing to chronic renal failure develops in 30-40% of individuals with type I diabetes and 5-10% of individuals with type II diabetes. As such, diabetic neuropathy is perhaps the major determinant of premature mortality in the type I diabetic. The renal disease characteristic of diabetes mellitus is marked by glomerular hypertension and mesangial cell hypertrophy and hyperplasia, as well as extensive remodeling of the glomerular basement membrane. These phenomena may arise as a result of the actions of vasoconstrictive vasoactive peptides, especially endothelin (ET-1) and angiotensin-II (A-II). In addition, hyperglycemia itself, along with the physical stress of glomerular hypertension may contribute to glomerular hypertrophy and basement membrane remodelling. It has become clear that cellular signal transduction pathways play an important role in coupling vasoactive peptides to the biological consequences of diabetic neuropathy. Indeed, hyperglycemia, ET-1, and A-II, as well as mechanical/hypertensive stress can induce c-fos and c-jun. Thus a complete understanding of the cellular signal transduction mechanisms recruited by vasoactive peptides, hypertensive stress, and reperfusion inhjury is crucial to the development of more effective treatments for diabetic neuropathy. The investigators have identified two signaling networks which are strongly activated by ET-1 and hypertensive stress (cell stretching). These pathways have been shown to mediate fos and jun induction in response to a variety of stresssful stimuli by recruiting two subfamilies of the extracellular signal-regulated kinases (ERKs), the stress-activated protein kinases (SAPKs, also called JNKs) and p38. It is the goal of the next phase of this project to determine how the SAPKs and p38s are regulated by the divergent stresses of ET-1, cell stretching, and reperfusion injury, and how the SAPKs and p38 contribute to the pathogenesis of diabetic neuropathy. First, the investigator will use a combination of conventional biochemical assays to identify members of the mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) family, presen in mesangial cells which activate the SAPKs and p38 and which are themselves regulated by ET-1, A-II, or cell stretching. Next, they will determine the mechanisms by which A-II, ET-1, and cell stretching in mesangial cells recruit G proteins to activate the SAPKs and p38s. In particular they will focus on trimeric and Ras superfamily G proteins, as well as MEK-kinase-1 (MEKK1), a Ser/thr kinase also thought to regulate the SAPK pathway. Finally, they will use adenoviral expression constructs to perturb SAPK and p38 activation in mesangial cells and examine the effects of these perturbations on two biological responses known to occur in mesangial cells during diabetic nephropathy: cellular hypertrophy and excess matrix deposition. These studies, they hope, will expand our knowledge of signal transduction in the diabetic kidney and contribute to the development of novel treatments for diabetic nephropathy using signaling components as targets.
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