Effect of glycine on cisplatin nephrotoxicity and heat-shock protein 70 expression in the rat kidney.
Glycine has been shown to protect against cisplatin (CP) nephrotoxicity in rats and to enhance the in vitro expression of heat-shock protein (hsp) 70 in renal epithelial cells following sublethal heat shock. We hypothesized that the protective effect of glycine against CP nephrotoxicity may be due to an up-regulation of Hsp 70 protein expression. Male Sprague-Dawley rats were divided into 4 treatment groups based upon infusion of glycine and injection of CP or their respective vehicles. At 5 days after treatment animals administered CP alone demonstrated a significant decrease in creatinine clearance compared to baseline (0.77 +/- 0.32 mL/min vs. 3.90 +/- 0.87 mL/min, p < 0.05). Treatment with glycine and CP attenuated this response, with no significant decline seen in creatinine clearance at day 5 compared to baseline (2.25 +/- 0.31 mL/min vs. 3.40 +/- 0.86 mL/min). Semiquantitative histological study revealed a marked decrease in proximal tubular injury at the juxtamedullary and outer medullary regions among animals treated with glycine and CP compared to those animals treated with CP alone. There were no differences in renal cortical and medullary Hsp 70 levels by Western immunoblotting between animals treated with glycine and CP compared to CP alone at 4 h and 5 days after treatment. Immunohistochemical studies of animals treated with CP alone revealed the diffuse presence of Hsp 70 in the cytoplasm of injured and necrotic proximal tubular cells 5 days after treatment. Animals receiving CP and glycine demonstrated a more focal presence of Hsp 70 restricted to injured proximal tubular cells, with no staining of uninjured cells. The protective effect of glycine in CP-induced acute and renal failure in the rat does not appear to be associated with enhancement of Hsp 70 expression.
Musio
F
F
Nephrology Service, Walter Reed Army Medical Center, Washington, DC 20307-5001, USA.
Carome
M A
MA
Bohen
E M
EM
Sabnis
S
S
Yuan
C M
CM
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D015153:Blotting, Western; D002945:Cisplatin / Q000633:toxicity*; D005998:Glycine / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D002945:Cisplatin; D005998:Glycine