I am working on the effect of altered excretion of ADME profile of AED. I am trying to induce the renal damage in rats so as to alter the excretory system. Please tell me what is the mechanism behind cyclosporine induced renal damage nd also suggest some other drug induced renal toxicity animal models.
I am pretty sure the renal toxicity is due to inhibition of calcinerin. CyA binds to the cyclophilin/calcineurin complex and inhibits calcineurin's ability to phosphorylate proteins. I can't remember what the target protein is for calcineurin for renal toxicity, however. I will look it up, though.
you can try this link.
Cyclosporine and tacrolimus nephrotoxicity - UpToDate
www.uptodate.com/contents/cyclosporine-and-tacrolimus-nephrotoxicity
CsA induces TGF-β synthesis, this last one stimulates cells to increase their extracellular matrix composition inducing a profibrogenic state. CsA-induced nephrotoxicity has the characteristics of interstitial fibrosis (Matsuda, 2000; Massague, 1990). You may want to review more recent data as well
Is it through Calcineurin inhibition leading to SMAD activation, Alice? I saw a couple of papers on this topic. It makes total sense now. Thanks
Cyclosporine A, which has been the foremost immunosuppressive agent since the early 1980’s, significantly improves the success of organ transplantation. However, common complications of cyclosporine A therapy, such as severe renal tubulointerstitial fibrosis, limit the drug’s clinical use. Although the exact mechanisms driving cyclosporine A-induced tubulointerstitial fibrosis remain elusive, we hypothesized that epithelial-mesenchymal transition (EMT) may play a major role. We investigated this in vitro by treating human proximal tubular cells with cyclosporine A. Morphological changes were observed after cyclosporine A treatment, including cell elongation (with a large degree of detachment), cytoskeletal rearrangement, and junctional disruption. In addition, expression of the myofibroblast-specific marker α-smooth muscle actin was detected in treated cells. These observations are consistent with events described during EMT. Using Affymetrix gene microarrays, we identified 128 genes that were differentially regulated in renal tubular cells after cyclosporine A treatment, including known profibrotic factors, oncogenes, and transcriptional regulators. Cyclosporine A induced a dose-dependent increase in transforming growth factor-β secretion from proximal tubular cells. Subsequent functional studies revealed that protein kinase C-β isoforms play a key role in cyclosporine A-induced effects. These findings provide novel insights into cyclosporine A-induced renal fibrosis and the molecular mechanisms underlying EMT, events that may be relevant in other disease states.
Fore more plz read the attached article.
- Badges
- Science topic
- Similar topics
- Chemistry
- Pharmacology