Cyclosporine effects on isolated membranes, proximal tubule cells, and interstitium of the kidney.
The pathogenesis of renal cell injury is a complex interplay among derangements in subcellular membrane function and mediators of injurious processes. Plasma and subcellular membrane injury and the resulting membrane dysfunction appear especially important. As detailed previously in this report, Cs, an extremely lipophilic compound, has the ability to bind to renal brush border membranes, interact with mitochondrial membranes resulting in multiple sites of dysfunction, and accumulate in high concentrations in renal proximal tubule cells. In spite of these interactions, Cs could not be shown to be directly toxic in vitro to proximal tubule cells. Thus, from these experiments, it is difficult to conclude that Cs-induced acute renal failure observed in vivo is due to a direct tubular toxic effect, even though Cs has the capability to interact with critical renal membranes at low concentrations. The majority of present evidence, therefore, does not suggest a toxic effect of Cs on renal epithelial cells. Instead, the acute effect of Cs to produce a decline in renal excretory function appears to be due to a fall in renal blood flow. On the other hand, the chronic effect of Cs to produce a decline in renal excretory function appears to be due to an effect of this agent to induce interstitial fibrosis. In this regard, recent findings summarized in this report demonstrate that Cs produces (over ten days) a higher than normal collagen content, as measured by hydroxyproline levels, in the kidney. In addition, this increase in collagen content with Cs treatment was associated with a significant increase in proliferation of cells in the renal interstitium, as determined by 3H-thymidine incorporation into DNA. This increase in DNA incorporation after Cs was not observed in other organs, including liver, spleen, or heart. Histologic assessment of these proliferating cells revealed them to be mononuclear. Cell surface markers also demonstrated an increase in LCA positive cells in the renal interstitium. These results, therefore, suggest a readily demonstrable effect of Cs on the renal interstitium. The relationship between Cs dosage and interstitial cell proliferation as well as the relationship between Cs-induced renal perfusion alterations and this interstitial proliferative process mandates further investigation.
Humes
H D
HD
Veterans Administration Medical Center, Ann Arbor, MI 48105.
Jackson
N M
NM
D000818:Animals; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects*; D007672:Kidney Cortex / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D008871:Microvilli / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats
D003524:Cyclosporins; D003094:Collagen