Fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) such as collagen and fibronectin in and around damaged tissue, which can lead to permanent scarring, organ malfunction and, ultimately, death. Although we have advanced our understanding of the pathogenesis of kidney fibrosis the translation of these findings to humans has been limited and no proven therapeutic strategies can yet detect or prevent the disease progression. We discovered Secreted Protein Acidic and Rich in Cysteines (SPARC) related modular calcium binding 2 (SMOC2) to be amongst the highest upregulated genes in the kidneys of mice subjected to chronic progressive kidney fibrosis. The mRNA and protein levels of SMOC2 were confirmed to be increased (10 to 60-fold) in three mechanistically distinct mouse models of kidney fibrosis as well as in patients with biopsy-proven kidney fibrosis. In the human fibrotic kidney, SMOC2 was concentrated in epithelial cells of the tubular region while also dispersed around the ?-Smooth Muscle Actin positive myofibroblasts of the interstitial tissue. In cell culture experiments, recombinant SMOC2 activated fibroblasts to proliferate and migrate - features typical of transitioning into the effector cell of repair ? Myofibroblast. SMOC2 treatment of primary human proximal tubular epithelial cells significantly increased vimentin staining (a marker of epithelial cell de-differentiation) along with an increase in cell size ? typical of epithelial to mesenchymal transition (EMT); coupled with a decrease in cell number (features of the profibrotic TGF? pathway). We also found that transgenic mice overexpressing SMOC2 showed significantly enhanced tubulointerstitial fibrosis characterized by substantially higher myofibroblast activation, neutrophil infiltration and collagen accumulation following unilateral ureteral obstruction-induced kidney fibrosis. These results have led us to hypothesize that SMOC2 is a key signaling molecule in the pathological secretome of a damaged kidney that plays a critical role in the reparative scaffold; whose continual presence leads to fibrosis. The objective here is to investigate how induction of SMOC2 in fibroblasts and epithelial cells regulate initiation and progression of kidney fibrosis and whether genetic or pharmacologic modulation of SMOC2 is capable of altering the ultimate outcome from kidney fibrosis. Given that there is no information on the functional significance of SMOC2 upregulation following kidney damage the proposed studies aim at uncovering a novel pathway which may provide opportunities for targeted therapies for patients with kidney fibrosis ? an unmet medical need.