Cellular Mechanisms of Renal Interstitial Fibrosis

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DESCRIPTION (provided by applicant): Progression of renal disease leads to common consequences including interstitial fibrosis, glomerulosclerosis, vascular narrowing, and renal failure, ultimately requiring dialysis or renal transplantation. The kidney myofibroblast is the cell type most responsible for matrix accumulation during renal fibrosis. Although there is a large amount of data on mechanisms of interstitial myofibroblast matrix synthesis late in the course of renal fibrosis, information on the earliest cellular events involving myofibroblast encroachment into the perivascular and interstitial spaces prior to matrix accumulation is lacking. Experiments are proposed to examine mechanisms of myofibroblast encroachment (migration and proliferation) in a model of accelerated renal fibrosis in which myofibroblasts first originate from perivascular and periglomerular regions. Our central hypothesis is: Activation of PDGFR-2 and TGF-beta receptor induces fibroblast migration and proliferation into the peritubular interstitium via Rho/ROCK modulated ROS generation and transduction of PI3-kinase/Akt, MAPK (ERK1/2) signaling pathways early during the progression of renal fibrosis. The following aims are set: Aim 1. NAD(P)H oxidase-derived ROS are involved in myofibroblast interstitial encroachment early during the course of kidney fibrosis; Aim 2. ROS-induced interstitial myofibroblast migration, proliferation and matrix synthesis is a consequence of PDGFR-2 and TGF- beta receptor activation; Aim 3. ROS generation through PDGFR-2 and TGF-2 receptor regulate SMAD2/3, Rho/ROCK, ERK1/2 and Akt signaling cascades, initiating interstitial myofibroblast migration, proliferation, and matrix synthesis. PDGF BB and TGF2-1 initiate ROS generation in vascular disease. Experiments are designed to critically examine a role for NAP(P)H oxidase and associated phox subunits in ROS generation, PDGFR-2 and TGF-2 receptor activation and signaling pathways on myofibroblast migration, proliferation and matrix synthesis in vitro and in vivo. Specifically, a role for the NAD(P)H oxidase pathway (Nox2 and Nox4 and phox subunits) will be examined in PDGFR-2 and TGF-2 receptor transduction of SMADs, Rho/ROCK, PI3K, and ERK1/2 regulation of activation of kidney myofibroblast. These studies will provide much needed insight on mechanisms of myofibroblast activation during the early stages of renal fibrosis. PUBLIC HEALTH RELEVANCE: To date, the majority of research on renal interstitial fibrosis has focused on late changes associated with matrix accumulation, with little attention on early events of myofibroblast encroachment (migration and proliferation) into the interstitium. Understanding the mechanisms of myofibroblast encroachment before fibrosis occurs could lead to new therapies in the early treatment of chronic renal disease. This application focuses on a role for reactive oxygen species (ROS) in renal myofibroblast encroachment early during the initial stages of fibrosis.