Effects of anti-proteinuric therapy with angiotensin-converting-enzyme inhibition on renal protein catabolism in the adriamycin-induced nephrotic rat.
A direct consequence of glomerular protein leakage is an increased exposure of proximal tubular cells to proteins. The aim of the present study was to examine whether chronic proteinuria affects the tubular handling of proteins and whether anti-proteinuric therapy by angiotensin-converting-enzyme (ACE) inhibition restores this tubular function. Renal uptake and catabolic rate of the low-molecular-weight protein (LMWP) myoglobin was determined in anaesthetized control and adriamycin-induced nephrotic rats by external counting after radiolabelling. Proteinuria correlated with the uptake as well as the catabolism of myoglobin. The higher the proteinuria, the lower was the renal uptake of myoglobin (r =0.72, P =0.002). Also, the catabolic rate of myoglobin (r =0.80, P =0.0002) was lower with increasing severity of proteinuria. During treatment with the ACE inhibitor lisinopril, proteinuria was lowered by 79+/-9% (mean+/-S.E.M.). Renal uptake and catabolic rate of the LMWP were not restored by ACE inhibition. The catabolic rate of myoglobin was even decreased further with 48+/-5% compared with pretreatment levels. In summary, adriamycin-induced proteinuria is associated with a lower uptake and a lower catabolic rate of LMWP in the proximal tubule. ACE inhibition lowers proteinuria, but does not restore the affected LMWP uptake and rate of catabolism. The rate of LMWP catabolism is even decreased further. In contrast, the urinary excretion of N -acetyl glucosaminidase, the tubular marker of toxicity, was effectively returned to normal levels during ACE inhibition. Taken together, the data suggest that proteinuria is toxic for the proximal tubular cells and that ACE inhibition protects the remaining functional tubular cells directly against destruction through decreasing hypercatabolism.
Haas
Marijke
M
Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration, University of Groningen, P.O. Box 196, NL-9700 AD Groningen, The Netherlands.
de Boer
Eric
E
de Jong
Paul E
PE
Moolenaar
Frits
F
Meijer
Dirk K F
DK
de Zeeuw
Dick
D
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D007457:Iodine Radioisotopes; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D017706:Lisinopril / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D009211:Myoglobin / Q000378:metabolism*; D009401:Nephrosis / Q000188:drug therapy / Q000378:metabolism*; D011507:Proteinuria / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000806:Angiotensin-Converting Enzyme Inhibitors; D000903:Antibiotics, Antineoplastic; D007457:Iodine Radioisotopes; D009211:Myoglobin; D004317:Doxorubicin; D017706:Lisinopril