leupeptins and Kidney-Diseases

So far, cardiovascular and renal diseases have brought us not only huge economic burden but also serious society problems. Since effective therapeutic strategies are still limited, to find new methods for the prevention or therapy of these diseases is important. Oxidative stress has been found to play a critical role in the initiation and progression of cardiovascular and renal diseases. In addition, activation of nuclear-factor-E2-related-factor-2- (Nrf2-) antioxidant-responsive element (ARE) signaling pathway protects cells and tissues from oxidative damage. As a proteasomal inhibitor, MG132 was reported to activate Nrf2 expression and function, which was accompanied with significant preventive and/or therapeutic effect on cardiovascular and renal diseases under most conditions; therefore, MG132 seems to be a potentially effective drug to be used in the prevention of oxidative damage. In this paper, we will summarize the information available regarding the effect of MG132 on oxidative stress-induced cardiovascular and renal damage, especially through Nrf2-ARE signaling pathway.

Topics: Animals; Antioxidant Response Elements; Cardiovascular Diseases; Humans; Kidney Diseases; Leupeptins; NF-E2-Related Factor 2; Oxidative Stress; Proteasome Endopeptidase Complex; Signal Transduction; Ubiquitin

Transforming growth factor-β (TGF-β) is involved in renal tubulointerstitial fibrosis. Recently, the ubiquitin proteasome system was shown to participate in the TGF-β signalling pathway. The aim of this study was to examine the effects of proteasome inhibitors on TGF-β-induced transformation of renal fibroblasts and tubular epithelial cells in vitro and on unilateral ureteral obstruction (UUO) in vivo.. Rat renal fibroblasts NRK-49F cells and tubular epithelial cells, NRK-52E, were treated with TGF-β in the presence or absence of a proteasome inhibitor, MG132 or lactacystin. Rats were subjected to UUO and received MG132 i.p. for 7 days.. In cultured renal cells, both MG132 and lactacystin inhibited TGF-β-induced α-smooth muscle actin (α-SMA) protein expression according to both western blotting and immunofluorescent study results. MG132 also suppressed TGF-β-induced mRNA expression of α-SMA and upregulation of Smad-response element reporter activity. However, MG132 did not inhibit TGF-β-induced phosphorylation and nuclear translocation of Smad2. In contrast, MG132 increased the protein level of Smad co-repressor SnoN, demonstrating that SnoN is one of the target molecules by which MG132 blocks the TGF-β signalling pathway. Although the proteasome inhibitor suppressed TGF-β-induced transformation of cultured fibroblasts and tubular epithelial cells, MG132 treatment did not ameliorate tubulointerstitial fibrosis in the rat UUO model.. Proteasome inhibitors attenuate TGF-β signalling by blocking Smad signal transduction in vitro, but do not inhibit renal interstitial fibrosis in vivo.

Topics: Acetylcysteine; Actins; Animals; Cells, Cultured; Cysteine Proteinase Inhibitors; Disease Models, Animal; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibroblasts; Fibrosis; Kidney Diseases; Leupeptins; Male; Nerve Tissue Proteins; Rats; Rats, Wistar; RNA, Messenger; Signal Transduction; Smad Proteins, Receptor-Regulated; Smad2 Protein; Smad3 Protein; Smad4 Protein; Transcription Factors; Transcription, Genetic; Transforming Growth Factor beta; Ureteral Obstruction

alpha 2u-Globulin, a protein of hepatic origin found in the urine of male rats, is accumulated in the kidney cortex during exposure to unleaded gasoline and has been implicated in the development of fuel hydrocarbon-induced nephropathy and renal neoplasia. The principal morphological feature of gasoline-induced nephropathy is accumulation of hyaline droplets (enlarged secondary lysosomes or phagolysosomes) in epithelial cells of the proximal convoluted tubule S1 and S2 segments. Inhibition of cathepsin B (a major lysosomal peptidase) by treatment of male rats with leupeptin causes rapid accumulation of phagolysosomes and alpha 2u-globulin in the kidney very similar to gasoline exposure. Further, the renal cortical subcellular distribution of alpha 2u-globulin, determined with an electron microscopic immunochemical method, is almost totally confined to phagolysosomes following administration of either gasoline or leupeptin. These results, taken together, indicate that the mechanism of nephrotoxicity of gasoline involves inhibition of renal phagolysosomal proteolysis.

Topics: Alpha-Globulins; Animals; Gasoline; Kidney; Kidney Diseases; Leupeptins; Male; Oligopeptides; Petroleum; Phagosomes; Proteins; Rats; Rats, Inbred F344

Lysosomal involvement in renal tubular lesions was studied mainly by electronmicroscopy after single and repeated administrations of cephacetrile, cephalothin, cephaloridine, gentamicin or leupeptin and combine administrations of cephalothin and gentamicin or gentamicin and leupeptin in female Wistar rats. Large cytosomes of high density were increased due probably to either reabsorption and secretion of drugs or their metabolites. These cytosomes displaying acid phosphatase activity were demonstrated histochemically and were identified as heterolysosomes. In rats treated with cephaloridine, gentamicin or leupeptin, disruption of lysosomal membrane was noted and regional cytoplasmic destruction was seen in the vicinity of the disrupted heterolysosomes. Necrotic epithelial cells and renal insufficiency were observed in these animals. On the other hand, neither destruction of lysosomes nor cell lesion was found in rats treated with cephacetrile or cephalothin. It was speculated that lysosomal destruction might be the cause of the cell lesions found in cephaloridine, gentamicin or leupeptin treated rats.

Topics: Animals; Anti-Bacterial Agents; Cephacetrile; Cephaloridine; Cephalothin; Female; Gentamicins; Kidney Diseases; Kidney Tubules; Leupeptins; Lysosomes; Rats