Glomerular abundance of nephrin and podocin in experimental nephrotic syndrome: different effects of antiproteinuric therapies.
Nephrotic syndrome (NS) is a clinical state characterized by massive proteinuria, hypoalbuminemia, and eventual edema formation. Although the mechanisms underlying this phenomenon are not yet fully clarified, it is well accepted that nephrin and podocin are involved in the development of proteinuria. The effects of early treatment with various antiproteinuric therapies on proteinuria and glomerular staining of nephrin and podocin in rats with experimental NS have not been previously studied. Proteinuria and glomerular nephrin and podocin immunofluorescence were examined in rat kidneys with adriamycin-induced NS and the effects of antiproteinuric drug therapies during 5 wk with enalapril, losartan, alone or in combination, omapatrilat, and mycophenolate mofetil on these parameters were assessed. Injection of adriamycin caused a significant increase in daily (from 21.8 +/- 1.4 to 983.1 +/- 45.8 mg/day, P < 0.01) and cumulative protein excretion (from negligible values to 22,490 +/- 931 mg, P < 0.001) during 5 wk. Early treatment with enalapril significantly decreased the daily (641.7 +/- 82.4 mg/day, P < 0.0023) and cumulative proteinuria (15,727 +/- 2,204 mg, P < 0.001). A similar effect, although to a lesser extent, was obtained after omapatrilat treatment: cumulative proteinuria was reduced to 18,706 +/- 1,042 mg, P < 0.001. In contrast, losartan treatment did not significantly influence the cumulative proteinuria that remained comparable (20,351 +/- 1,360 mg, P > 0.05) to that observed in untreated NS rats. Unexpectedly, when losartan was given in combination with enalapril, it abolished the beneficial effects of the latter. Pretreatment with mycophenolate mofetil exerted a moderate antiproteinuric effect, which appeared only during the last week of the experimental treatment. Nephrotic rats exhibited severe disruption of slit diaphragm structure as seen by rapid and profound loss of nephrin and podocin. Beneficial effects of enalapril, omapatrilat, and mycophenolate mofetil paralleled the preservation of nephrin, as determined immunohistochemically, and enabled prediction of significant antiproteinuric responses. Enalapril alone or in combination with losartan resulted in significant preservation of podocin. Pretreatment with enalapril, and to a lesser extent omapatrilat, is superior to losartan in reducing proteinuria in NS rats. A combination of ACE inhibitors with ANG II receptor blockers does not provide any advantageous antiproteinuric therapy in these animals. Nephrin loss is an indication of proteinuria in NS and the antiproteinuric effects of ACE inhibitors, vasopeptidase inhibitors, and mycophenolate mofetil attenuate this reduction. Not all the drugs which restore podocin reduce urinary protein in NS.
Nakhoul
Farid
F
Dept. of Physiology and Biophysics, Faculty of Medicine, Technion, P.O. Box 9649, Haifa, 31096, Israel.
Ramadan
Rawi
R
Khankin
Eliyahu
E
Yaccob
Afif
A
Kositch
Zoya
Z
Lewin
Moshe
M
Assady
Suheir
S
Abassi
Zaid
Z
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D004317:Doxorubicin / Q000627:therapeutic use; D015773:Enalaprilat / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D009404:Nephrotic Syndrome / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011500:Protein Synthesis Inhibitors / Q000627:therapeutic use; D011507:Proteinuria / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013841:Thiazepines / Q000627:therapeutic use
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; D013841:Thiazepines; C113267:nephrin; C106266:omapatrilat; D004317:Doxorubicin; D015773:Enalaprilat; D009173:Mycophenolic Acid; D019808:Losartan