Alterations in proteolytic enzymes of the proximal tubule in a rat model of cyclosporine nephrotoxicity.
The presence of autophagolysosomes in proximal tubule cells and the increased urine excretion of the lysosomal enzyme N-acetyl-glucosaminidase following administration of cyclosporine suggests involvement of the lysosomes in tubular toxicity of CsA. To evaluate the effect of CsA on lysosomal function, the activity of the lysosomal proteinases cathepsin B and L was measured in microdissected segments of the proximal tubule by means of a fluorometric microassay. Rats received oral doses of 30 mg/kg CsA for eight weeks. Controls received olive oil. CsA reduced renal blood flow, glomerular filtration rate, and kidney weight. Hence, a second control group was included where the left renal artery was clipped to reduce RBF and GFR. CsA administration was accompanied by a 130% increase in cathepsin activities in the S1 segments of the proximal convoluted tubule. The activity remained unchanged in the pars recta. Enzyme activities in convoluted proximal tubules and pars recta from the control groups were not increased irrespective of reduced RBF, decreased GFR, and decreased KW. Hence, cathepsin B and L stimulation was induced by CsA per se. Since lysosomes are involved in cellular protein catabolism, the increased cathepsin activities may reflect an increased rate of protein breakdown. The tubular atrophy induced by CsA may be related to increased intracellular protein degradation.
Olbricht
C J
CJ
Department of Nephrology, Medical School Hannover, Federal Republic of Germany.
Gröne
H J
HJ
Bossaller
C
C
Gutjahr
E
E
Hertel
R F
RF
D000818:Animals; D001783:Blood Flow Velocity; D002401:Cathepsin B / Q000378:metabolism*; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism*; D003524:Cyclosporins / Q000494:pharmacology / Q000633:toxicity*; D003546:Cysteine Endopeptidases; D004195:Disease Models, Animal; D010450:Endopeptidases; D005919:Glomerular Filtration Rate; D007674:Kidney Diseases / Q000139:chemically induced; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012078:Renal Artery Obstruction
D003524:Cyclosporins; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; D056668:Cathepsin L; C534280:Ctsl protein, rat