| | |  | | | | Record from Web of Science® | | | | | | |
| CELLULAR AND MOLECULAR MECHANISMS OF CYCLOSPORINE NEPHROTOXICITY |
|
|
| Author(s): KOPP JB, KLOTMAN PE |
| Source: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Volume: 1 Issue: 2 Pages: 162-179 Published: AUG 1990 |
| Times Cited: 147 References: 175 |
| Abstract: Cyclosporin therapy is associated with several forms of nephrotoxicity, the most significant of which are reversible impairment of glomerular filtration and irreversible interstitial fibrosis. Impaired glomerular filtration is due to both reduction in K(f), the glomerular capillary ultrafiltration coefficient, and to reduction in renal blood flow. The mechanisms responsible for the low K(f) are not well defined, but heightened mesangial cell contractility may contribute. Reduced renal blood flow with chronic cyclosporin therapy arises from both endothelial damage and altered eicosanoid metabolism, in particular increased thromboxane synthesis. Renal interstitial fibrosis, which develops in some patients after approximately 6-12 months of cyclosporin therapy, poses a major limitation to the chronic use of the drug. Two mechanisms likely contribute to cyclosporin-associated interstitial fibrosis. First, endothelial injury and vasoconstriction produce renal ischemia, which in turn is associated with enhanced synthesis of extracellular matrix proteins. Second, cyclosporin likely influences the accumulation of matrix proteins in the renal interstitium through nonhemodynamic mechanisms, as suggested by altered matrix accumulation in nonrenal tissues. This effect of cyclosporin may be direct or indirect, via mediators including cytokines, peptide growth factors, and thromboxane. The molecular mechanisms of cyclosporin action on immunologic and mesenchymal cells are active areas of investigation. Intracellular targets of cyclosporin include mitochondrial respiration, cellular calcium signaling, protein kinase C, protein synthesis, and peptidyl-prolyl isomerases. However, the significance of these intracellular effects for cyclosporin nephrotoxicity remains to be demonstrated. |
| Document Type: Article |
| Language: English |
Addresses:
1. NIDR, DEV BIOL & ANOMALIES LAB, MOLEC MED SECT, BETHESDA, MD 20892 USA |
| Publisher: WILLIAMS & WILKINS, 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 |
| Subject Category: Urology & Nephrology |
| IDS Number: FT093 |
| ISSN: 1046-6673 |
|
| | | | | | | | | Record from Web of Science® | | | | | | | | | |