| The objective of this study was to characterize the tissue repair response with regard to dose-response relationships, temporal effects, molecular regulation, and effects of modulation of the repair on recovery from renal injury and survival. S-(1,2-Dichlorovinyl)-L-cysteine (DCVC), a well established model nephrotoxicant, was used in our studies. The dose response studies suggested that a timely and adequate tissue repair rescues mice from renal proximal tubular injury after administration of low to moderate dose of DCVC. At the highest dose tissue repair was inhibited thereby causing acute renal failure (ARF) and death.; Inhibition of tissue repair by colchicine following a normally nonlethal dose of DCVC led to escalated renal injury and 100% mortality. Induction of compensatory tissue repair by prior administration of a low priming dose of DCVC (autoprotection model) or mercuric chloride (heteroprotection model), before administering a normally lethal dose of DCVC, resulted in 100% protection from death due to ARE These findings led to three questions: (1) Why does a high dose of DCVC inhibit tissue repair? (2) What molecular mechanisms stimulate tissue repair following a low to moderate dose of DCVC? and (3) Why is tissue repair sustained if a priming low dose of DCVC is given three days prior to the high dose?; In order to address the above three questions the role of extracellular signal-regulated kinases 1/2 (ERK1/2) pathway was investigated in DCVC-induced compensatory tissue repair. We report that the high (lethal) dose of DCVC downregulates the ERK1/2 cascade thereby inhibiting tissue repair whereas, the low (nonlethal) dose of DCVC stimulates it which is further sustained in the autoprotection model causing tissue repair and recovery from ARF.; We conclude: (a) Compensatory tissue repair is critical for recovery from ARF; (b) Although injury is essential for stimulation of tissue repair, it is not the extent of renal injury that determines the extent of tissue repair; (c) Modulation of tissue repair alters the ultimate outcome of nephrotoxicity; (d) Downregulation of ERK1/2 plays a predominant role in inhibition of tissue repair following high dose whereas stimulation and sustained activation of ERK 1/2 results in 100% survival from ARF in the autoprotection group. |
