Cisplatin-induced kidney injury in the rat: L-carnitine modulates the relationship between MMP-9 and TIMP-3.
Renal interstitial fibrosis is a major complication of cisplatin treatment, due to the increased accumulation of extracellular matrix (ECM) proteins whose remodeling is important for the development of normal tissues; indeed, its malfunction might play a role in the etiology of various diseases. Biopharmacological evaluations suggest that L-carnitine can prevent cardiac metabolic damage caused by doxorubicin, as well as can inhibit cisplatin-induced injury in the kidney and in the small intestine, without any interference with the drug's antitumoral properties. Since the glomerular basement membrane and the mesangial matrix constitute the ECM of the renal glomerulus, we examined the localization and expression of MMP-9 and TIMP-3 in normal rat kidney and the changes in their expression over a period of time by treatment with cisplatin, with and without L-carnitine. MMP-9 immunoreaction in cisplatin-treated rat kidney tissue suggests an involution of the basal membrane, an alteration of ECM components and low glomerular function, due to the increased thickness of the mesangium. Our results suggest that the matrix remodeling by MMP-9 and TIMP-3, in the later stages, can play an important role in the development of glomerular sclerosis and interstitial fibrosis after cisplatin treatment. It can also be postulated that L-carnitine protects from cisplatin injury, by modulating the relationship between MMP-9 and TIMP-3.
Martinez
Giuseppa
G
Department of Anatomy, Diagnostic Pathology, Forensic Medicine, Public Health Medical School, Catania University, Italy.
Costantino
Giuseppe
G
Clementi
Anna
A
Puglia
Michele
M
Clementi
Silvia
S
Cantarella
Giuseppina
G
De Meo
Leonardo
L
Matera
Mario
M
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D002331:Carnitine / Q000494:pharmacology*; D002945:Cisplatin / Q000633:toxicity*; D005920:Glomerular Mesangium / Q000201:enzymology; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000187:drug effects; D014803:Vitamin B Complex / Q000494:pharmacology*
D000970:Antineoplastic Agents; D019717:Tissue Inhibitor of Metalloproteinase-3; D014803:Vitamin B Complex; D020780:Matrix Metalloproteinase 9; D002945:Cisplatin; D002331:Carnitine