title: Diabetic mice are protected from normally lethal nephrotoxicity of S-1,2-dichlorovinyl-L-cysteine (DCVC): role of nephrogenic tissue repair.
abstract: Streptozotocin (STZ)-induced diabetic (DB) rats are protected from nephrotoxicity of gentamicin, cisplatin and mercuric chloride, although the mechanisms remain unclear. Ninety percent of DB mice receiving a LD90 dose (75 mg/kg, ip) of S-1,2-dichlorovinyl-l-cysteine (DCVC) survived in contrast to only 10% of the nondiabetic (NDB) mice surviving the same dose. We tested the hypothesis that the mechanism of protection is upregulated tissue repair. In the NDB mice, DCVC produced steep temporal increases in blood urea nitrogen (BUN) and plasma creatinine, which were associated with proximal tubular cell (PTC) necrosis, acute renal failure (ARF), and death within 48 h. In contrast, in the DB mice, BUN and creatinine increased less steeply, declining after 36 h to completely resolve by 96 h. HPLC analysis of plasma and urine revealed that DB did not alter the toxicokinetics of DCVC. Furthermore, activity of renal cysteine conjugate beta-lyase, the enzyme that bio-activates DCVC, was unaltered in DB mice, undermining the possibility of lower bioactivation of DCVC leading to lower injury. [3H]-thymidine pulse labeling and PCNA analysis indicated an early onset and sustained nephrogenic tissue repair in DCVC-treated DB mice. BRDU immunohistochemistry revealed a fourfold increase in the number of cells in S-phase in the DB kidneys even without exposure to DCVC. Blocking the entry of cells into S-phase by antimitotic intervention using colchicine abolished stimulated nephrogenic tissue repair and nephro-protection. These findings suggest that pre-placement of S-phase cells in the kidney due to diabetes is critical in mitigating the progression of DCVC-initiated renal injury by upregulation of tissue repair, leading to survival of the DB mice by avoiding acute renal failure.
authors.affiliation: Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209-0470, USA.
authors.forename: Ankur V
authors.initials: AV
authors.lastname: Dnyanmote
authors.forename: Sharmilee P
authors.initials: SP
authors.lastname: Sawant
authors.forename: Edward A
authors.initials: EA
authors.lastname: Lock
authors.forename: John R
authors.initials: JR
authors.lastname: Latendresse
authors.forename: Alan A
authors.initials: AA
authors.lastname: Warbritton
authors.forename: Harihara M
authors.initials: HM
authors.lastname: Mehendale
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001806:Blood Urea Nitrogen; D001973:Bromodeoxyuridine / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003078:Colchicine / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D003545:Cysteine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008190:Lyases / Q000378:metabolism; D008297:Male; D051379:Mice; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012038:Regeneration / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D013311:Streptozocin; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D014316:Tritium; D013311:Streptozocin; C039961:S-(1,2-dichlorovinyl)cysteine; D003404:Creatinine; D008190:Lyases; D001973:Bromodeoxyuridine; D003545:Cysteine; D003078:Colchicine; D013936:Thymidine