Virtually all forms of progressive renal disease are characterized by excessive deposition of collagen IV. The lack of effective therapies for chronic renal disease are in large part due to a lack of understanding of basic mechanisms of fibrogenesis. Although TGF-beta1 has emerged as a predominant mediator of extracellular matrix production, the intracellular signaling pathways elicited by TGF-beta1 and the mechanism by which TGF-beta1 stimulates transcription of the collagen IV genes in pathophysiologic states is not known. We are currently delineating points of functional crosstalk between the Smad signaling pathways and the MAPK signaling pathways, and how these pathways culinate in transcriptional activation of the collagen IV genes. In parallel studies, we have recently found that agonists of the cAMP-PKA system are effective in inhibiting mesangial cell proliferation and matrix synthesis in response to acute renal injury. We are testing the hypothesis that the cAMP-PKA system may provide negative crosstalk with critical mitogenic, inflammatory, and matrix signaling pathways and may thereby prevent the onset and development of progressive renal disease. In collaboration with the Transplant Center, we are attempting to develop better prognostic markers, which will predict the development of renal fibrosis in allograft recipients.