Diabetic mice are protected from normally lethal nephrotoxicity of S-1,2-dichlorovinyl-l-cysteine (DCVC): role of nephrogenic tissue repair
Introduction
Modulation of nephrotoxicity in diabetes (DB) has been a topic of several investigations. Risk of contrast media-induced nephropathy (CMN) increases in patients with preexisting renal insufficiency including DB-nephropathy (Lautin et al., 1991, Rudnick et al., 1995, Suen et al., 1998, Andrew and Berg, 2004). Interestingly, Weisberg et al. (1999) report that DB patients are not anymore sensitive to hospital-acquired acute tubular necrosis (ATN) than non-diabetic (NDB) patients unless they suffer from cardiovascular disease. However, incidence of CMN increased in the DB patients when the contrast medium was used in combination with vasodilator and/or diuretic drugs (Weisberg et al., 1994).
Experimental DB has been shown to protect against the nephrotoxic effects of gentamicin, cisplatin, mercuric chloride, and cephaloridine (Vaamonde et al., 1984, Elliott et al., 1985, Valentovic et al., 1991, Cacini et al., 1993, Grover et al., 2002). Detailed investigations have been conducted using gentamicin and cisplatin in DB rats and rabbits (Vaamonde et al., 1984, Elliott et al., 1985, Valentovic et al., 1991, Cacini et al., 1993, Grover et al., 2002). These studies report reduced renal uptake/accumulation of the nephrotoxic drugs in DB kidneys. Although these studies suggested that lower renal concentration of the toxicants may be responsible for the protection in DB, the authors reported that this mechanism does not completely explain the protection in DB.
The possibility of other mechanisms playing a major role has been strongly suggested (Elliott et al., 1985, Gouvea et al., 1989, Scott et al., 1990, Valentovic et al., 1991, Sarangarajan and Cacini, 1996, Najjar and Saad, 2001). Collectively, these reports point out two principal observations: (1) gentamicin- and cisplatin-induced renal dysfunctions assessed by BUN and plasma creatinine elevations are lower in diabetic animals suggesting lower nephrotoxicity in diabetes; and (2) protection against nephrotoxicity of these drugs in diabetes cannot be completely explained by the reduced renal uptake of the toxicants. Time course profiles of renal dysfunction, histopathology, and whether or not DB-induced protection is reflected in animal survival from an ordinarily lethal challenge with nephrotoxicants may shed additional light. Moreover, such studies may reveal the role of other uninvestigated mechanisms such as augmented compensatory renal tissue repair in DB-induced protection, particularly since challenge with nephrotoxicants such as gentamicin, cisplatin, and mercuric chloride is known to stimulate a compensatory tissue repair response in the kidney (Dobyan et al., 1980, Haagsma and Pound, 1980, Laurent et al., 1988, Korrapati et al., 2005). The possibility that such repair mechanisms underlie DB-induced protection from nephrotoxicity is an attractive notion that warrants detailed investigation.
The present study focuses on three main objectives: (1) to study if STZ-induced DB protects against a normally lethal dose of S-1,2-dichlorovinyl-l-cysteine (DCVC) in mice; (2) to quantitate and characterize DCVC-induced renal dysfunction and injury over a time course in order to learn about the onset and recovery profiles of nephrotoxic injury; and (3) to test whether lower bioactivation, altered toxicokinetics, and enhanced compensatory tissue repair or a combination of all these factors play a critical role in this protection. A murine model of type 1 DB (Shankar et al., 2003a, Shankar et al., 2003b) was used to examine whether DB protects against the lethal nephrotoxicity of DCVC. This model of DB has been previously studied using three different strains of mice, which have been shown to be protected from hepatotoxicity of normally lethal challenge with thioacetamide (Shankar et al., 2003a), carbon tetrachloride, bromobenzene, and acetaminophen (Shankar et al., 2003c). Protection against thioacetamide (Shankar et al., 2003a) and acetaminophen-induced hepatic failure (Shankar et al., 2003c) could not be explained by lower bioactivation. Hepatoprotection was found to be due to early onset and robust compensatory hepatic tissue repair associated with stimulated PPAR-α activation in DB (Shankar et al., 2003b).
In the present study, we report that 90% of the DB mice survive a normally LD90 dose of DCVC (75 mg/kg ip). This remarkable protection does not appear to be due to altered disposition, higher elimination, or lower bioactivation of DCVC in the DB mice. Instead, the protection appears to come from a combination of mitigated progression of renal injury and an enhanced and sustained stimulation of tissue repair in DB mice. The mitigation of progressive expansion of renal injury may be attributed to DB-induced advancement of cells into cell division cycle even before challenge with the nephrotoxicant. Blocking this advancement of cells into S-phase using the antimitotic agent colchicine (CLC) resulted in progressive expansion of DCVC-initiated renal injury and abolition of DB-induced protection.
Section snippets
Animals
Male Swiss–Webster mice (25–29 g) were procured from Harlan Sprague–Dawley (Indianapolis, IN) and were maintained in our central animal facility under controlled conditions (temperature 21 ± 1 °C, relative humidity 50–80%, and 12 h light–dark cycle). The mice received commercial rodent chow (Harlan Teklad rodent diet 7012, Madison, WI) and water ad libitum and they were acclimatized for 1 week prior to use. All animal maintenance and treatment protocols were in compliance with the Guide for
Effect of DB on lethality of DCVC
Ninety percent of the NDB mice die between 36 and 48 h after treatment with 75 mg/kg of DCVC (Table 1). In contrast, only 10% of the DB mice receiving the same dose of DCVC died. No mortality was observed in the groups treated with DW vehicle used for DCVC or with STZ alone (Table 1). These findings were repeated and confirmed, indicating that DB affords marked protection against DCVC-induced toxicity. This finding formed the basis for additional studies to examine potential mechanisms of
Discussion
Protection from drug- and toxicant-induced nephrotoxicity has been investigated in experimentally induced DB in rats and rabbits using gentamicin, cisplatin, and mercuric chloride (Teixeira et al., 1982, Vaamonde et al., 1984, Elliott et al., 1985, Shyh et al., 1989, Cacini et al., 1993, Valentovic et al., 1997, Najjar and Saad, 2001, Grover et al., 2002). The authors suggested that lower renal accumulation of the toxicants in the DB kidney may play some role in the observed protection from
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