Glycocalyx thickness is reduced, glomerular endothelial cell pore size is increased, glomerular charge selectivity is reduced and

podocyte cell foot processes are fused. These changes are associated with reductions in glomerular cell production this website of proteoglycans and glycosaminoglycans contained within the glycocalyx produced by the glomerular endothelial cells.11 Further evidence for a direct effect of Adriamycin on the kidney comes from a study in which clipping of the renal artery of one kidney protects it from injury.20 Additional studies have examined the molecular mechanisms for Adriamycin-induced renal injury. Increased free radical production has been proposed as a pathogenetic mechanism. This is supported by isolation perfusion studies of hagfish (Myxine glutinosa) glomeruli Dinaciclib ic50 in which

Adriamycin was found to reduce glomerular ATPase activity in association with a reduction in water permeability, an effect reversed by the sulfhydryl donor N-acetylcysteine. In addition, depleted levels of glutathione (an anti-oxidant) and elevated levels of lipid peroxide levels in liver, kidney and heart developed after Adriamycin administration.60 Evidence for the role of advanced glycation end products comes from studies of receptor for advanced glycation end product (RAGE)-null mice. These mice are protected from Adriamycin-induced podocyte damage and proteinuria. Adriamycin induced generation of RAGE ligands, an effect reversed by treatment Miconazole with soluble RAGE. The mechanism for RAGE ligand-induced renal injury involved the activation of nicotinamide adenine dinucleotide phosphate-oxidase and p44/p42 MAP kinase signalling, and upregulation of pro-fibrotic growth factors.61 The changes associated with the slit diaphragm in Adriamycin-induced nephropathy have been studied by Otaki, Kawachi and colleagues.62 Early after Adriamycin administration (day 7), expression of the slit diaphragm

molecules nephrin, podocin and NEPH1 (but not ZO-1- and CD-associated protein) is altered from a continuous to a discontinuous dot-like pattern consistent with podocyte injury. In particular, NEPH1 was disproportionately affected. Using immunoprecipitation and western blot studies of glomerular lysates from animals 7 days after Adriamycin injection, Kawachi’s laboratory found that a large proportion of nephrin lost its affinity with NEPH1. While these data are observational in nature, they do point to slit diaphragm abnormalities as critical early events in the pathogenesis of Adriamycin-induced proteinuric renal injury. Gene profiling using microarray chip technology has identified gene networks that are potential drivers of tubulointerstitial fibrosis in AN.