Both the incidence and prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) are rapidly rising in the United States. Because renal interstitial fibrosis is highly predictive of progression to ESRD, there is an urgent need for anti-fibrogenic therapies. After injury, renal tubular epithelial cells transform into fibroblasts and/or myofibroblasts, via a process of epithelial-mesenchymal transition (EMT), which are capable of producing interstitial matrix proteins (e.g. type I collagen). Matrix metalloproteinase-2 (MMP-2) facilitates EMT in several epithelial cell types and has recently been shown to be directly responsible for renal tubular EMT as well. We hypothesize that MMP-2 inhibition will result in decreased renal tubular EMT and ultimately decreased interstitial fibrosis. We plan to test this hypothesis as follows: 1) Compare the degree of fibrosis after unilateral ureteral obstruction in MMP-2 -/- mice versus MMP-2 +/+ mice by measuring collagen content (histologically) and synthesis (real-time PCR), as well as markers of fibroblast/myofibroblast activation (IHC and real-time PCR for alpha-SMA and FSP-1), 2) Assess the role of MMP-2 in renal tubular EMT by comparing primary renal tubular epithelial cells isolated from MMP-2 -/- mice with those isolated from MMP-2 +/+ mice.
