Modulation of Matrix Metallo Proteases (MMPs) and MDM2 During Acute Dimethylnitrosamine (DMN)-Induced Nephrotoxicity in Mice

Tumor progression requires a continually evolving network of interactions between neoplastic cells and extracellular matrix (ECM). A relevant step of this process is the remodeling of microenvironment which surrounds tumors leading to the release of ECM-associated growth factors like MMPs and Plasmins. MMPs are zinc-requiring endopeptidases that are centrally involved in the controlled turnover of ECM components and are key to a varied range of developmental processes. Usually, carcinogens are known to orchestrate MMP release and perturb intercellular communication to override homeostatic control. Although these elements are instrumental to initiation of propagation of carcinogenesis, modulation of ECM and subsequent release of MMPs after acute toxicant exposure is not known. Thus, the goals of this study were to examine the expression of:

1. MMPs (especially 9, 10, and 12), and
2. MDM2 in the kidneys during DMN-induced nephrotoxicity.

Toxic doses of DMN (0, 25, 50 and 100 mg/kg; ip) were administered to 6 mo old male C3H mice and sacrificed 24h later. Besides serum BUN, liver homogenates were subjected to western blots to determine the levels of expression of MMPs (9, 10 & 12) and MDM2. Additional parameters of analysis included genomic changes(pattern of DNA fragmentation) and lipid peroxidation (oxidative stress). Data showed that DMN exposure caused a substantial dose-dependent increase in nephrotoxicity, oxidative stress, genomic injury and the expression of MMPs and MDM2. Thus, this study, for the first time, suggests involvement of MMPs/MDM2 during drug/chemical-induced organ injury and how they are influenced by genomic instability and oxidative stress. It is quite likely that MMPs and MDM2 participate in tissue remodeling during acute kidney injury.