Preplaced cell division: a critical mechanism of autoprotection against S-1,2-dichlorovinyl-L-cysteine-induced acute renal failure and death in mice.
Previous studies have shown that renal injury initiated by a lethal dose of S-1,2-dichlorovinyl-l-cysteine (DCVC) progresses due to inhibition of cell division and hence renal repair, leading to acute renal failure (ARF) and death in mice. Renal injury initiated by low to moderate doses of DCVC is repaired by timely and adequate stimulation of renal cell division, tubular repair, restoration of renal structure and function leading to survival of mice. Recent studies have established that mice primed with a low dose of DCVC (15 mg/kg i.p.) 72 h before administration of a normally lethal dose (75 mg/kg i.p.) are protected from ARF and death (nephro-autoprotection). We showed that renal cell division and tissue repair stimulated by the low dose are sustained even after the lethal dose administration resulting in survival from ARF and death. If renal cell division induced by the low dose is indeed the critical mechanism of this autoprotection, then its ablation by the antimitotic agent colchicine (1.5 mg CLC/kg i.p.) should abolish autoprotection. The present interventional experiments were designed to test the hypothesis that DCVC autoprotection is due to stimulated cell division and tissue repair by the priming low dose. CLC intervention at 42 and 66 h after the priming dose resulted in marked progressive elevation of plasma blood urea nitrogen and creatinine resulting in ARF and death of mice. Light microscopic examination of hematoxylin and eosin-stained kidney sections revealed progression of renal necrosis concordant with progressively failing renal function. With CLC intervention, S-phase stimulation (as assessed by BrdU pulse labeling), G(1)-to-S phase clearance, and cell division were diminished essentially abolishing the promitogenic effect of the priming low dose of DCVC. Phospho-retinoblastoma protein (P-pRB), a crucial protein for S-phase stimulation, and other cellular signaling mechanisms regulating P-pRB were investigated. We report that decreased P-pRB via activation of protein phosphatase-1 by CLC is the critical mechanism of this inhibited S-phase stimulation and ablation of autoprotection with CLC intervention. These findings lend additional support to the notion that stimulated cell division and renal tissue repair by the priming dose of DCVC are the critical mechanisms that allow sustained compensatory tissue repair and survival of mice in nephro-autoprotection.
Dept. of Toxicology, College of Pharmacy, The Univ. of Louisiana Monroe, 700 Univ. Ave., Sugar Hall no. 306, Monroe, LA 71209-0470, USA.
Midhun C
MC
Korrapati
Jaya
J
Chilakapati
Edward A
EA
Lock
John R
JR
Latendresse
Alan
A
Warbritton
Harihara M
HM
Mehendale
D000111:Acetylcysteine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology; D001806:Blood Urea Nitrogen; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D003078:Colchicine / Q000494:pharmacology; D003404:Creatinine / Q000652:urine; D018844:Cyclin-Dependent Kinases / Q000032:analysis / Q000502:physiology; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000032:analysis / Q000502:physiology; D054645:Protein Phosphatase 1; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors
D050256:Antimitotic Agents; C049705:S-1,2-dichlorovinyl-N-acetylcysteine; D004247:DNA; D003404:Creatinine; D018844:Cyclin-Dependent Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D003078:Colchicine; D000111:Acetylcysteine