Renal tissue can respond to loss of tissue by toxic tissue injury by stimulating renal tissue repair. Although the importance of the nephrogenic repair response is generally accepted, biochemical characterization of this process with regard to dose-response relationships, temporal effects, molecular regulation, and effects of modulation of the repair on recovery from renal injury and survival have not been investigated. In spite of the enormous renal reserve capacity, toxic renal failure and death can occur due to renal insufficiency. Clinicians would welcome life saving therapies that may help them in restoring renal function by replacing the lost tissue with functional tissue. This proposal is to investigate the mechanism of renal tissue repair using a well-established murine model of nephrotoxicity induced by S-(trans 1,2-dichlorovinyl) L-cysteine (DCVC). Preliminary studies indicate that renal tissue repair is dose-dependent, increases up to a threshold, and is inhibited beyond this threshold dose causing progression of renal injury leading to renal failure and animal death. Ablation of cell division response by administration of colchicine, well after the initiation of renal injury from an ordinarily non-lethal dose of DCVC, leads to progression of injury and animal death indicating the pivotal importance of cell division in tissue repair and recovery from limited initial injury. Furthermore, administration of a low dose of DCVC (15 mg/kg) 72 h before giving a normally lethal dose of DCVC resulted in complete protection from mortality (autoprotection), suggesting that preplaced tissue repair can avert renal failure and death. In these experiments, the possibility of protection by induction of metallothionein and priming dose will be fully tested. Objective of this proposal is to test the hypothesis that timely and adequate stimulation of cell division and tissue repair determines the toxic outcome of renal injury.
The specific aims are to: a) investigate the mechanism of autoprotection b) investigate if pretreatment by a low dose of mercuric chloride can protect mice (heteroprotection) from a lethal dose of DCVC; c) investigate if depletion of ATP underlies the reason for loss of cell division after a high dose and if restored ATP is the reason for autoprotection; and d) investigate molecular signaling mechanisms following a low dose, high dose, and also in the autoprotection group.
