Proinflammatory effects in experimental mesangial proliferative glomerulonephritis of the immunosuppressive agent SDZ RAD, a rapamycin derivative.
OBJECTIVE
The new immunosuppressant SDZ RAD, a rapamycin derivative, inhibits growth factor driven cell proliferation. SDZ RAD designed for transplantation may also be a candidate agent to treat inflammatory kidney diseases. Therefore, we investigated the effects of SDZ RAD in two different animal models of glomerulonephritis, in anti- Thy1.1 nephritis and in acute puromycin aminonucleoside (PAN) nephrosis.


METHODS
Eighty-seven male Wistar rats were investigated. Anti-Thy1.1 nephritis: healthy rats (n = 9), SDZ RAD-treated healthy rats (n = 6), nephritic rats (n = 9), SDZ RAD placebo treated nephritic rats (n = 6), SDZ RAD-pretreated nephritic rats (n = 9), and early (n = 6) as well as delayed (n = 6) SDZ RAD-posttreated nephritic rats. PAN nephrosis: healthy rats (n = 6), SDZ RAD-treated healthy rats (n = 6), nephritic rats (n = 12), and SDZ RAD-pretreated nephritic rats (n = 12). In a separate study, 12 male Sprague-Dawley rats were analyzed in anti-Thy1.1 nephritis: healthy rats (n = 3), nephritic rats (n = 3) and pretreated nephritic rats (n = 6). SDZ RAD and SDZ RAD placebo were given at single doses of 2.5 mg/kg body weight per day by gavage. The experiments lasted until days +2 and +9 after induction of anti-Thy1. 1 nephritis and until day +13 in the case of PAN nephrosis.


RESULTS
In anti-Thy1.1 nephritis, SDZ RAD demonstrated marked proinflammatory effects in a time-dependent manner, as reflected by severe focal damage to glomerular histology including inhibition of mesangial cell proliferation, reduction of creatinine clearance, and increase in plasma creatinine levels as well as proteinuria. Almost identical results were obtained in both rat strains. In contrary, SDZ RAD ameliorated significantly the development of PAN nephrosis. Animals pretreated by this agent showed a significant reduction of proteinuria and of glomerular invasion of monocytes/macrophages.


CONCLUSIONS
Some caution is warranted for the use of SDZ RAD in inflammatory glomerular diseases, since it accentuated glomerular damage induced by anti-Thy1.1 antibodies.
Daniel
C
C
Division of Nephrology and Hypertension, Department of Medicine, Inselspital, Bern, Switzerland.
Ziswiler
R
R
Frey
B
B
Pfister
M
M
Marti
H P
HP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D003176:Complement C3 / Q000187:drug effects / Q000378:metabolism; D015941:Complement Hemolytic Activity Assay; D000068338:Everolimus; D005920:Glomerular Mesangium / Q000187:drug effects / Q000473:pathology; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D009401:Nephrosis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011507:Proteinuria / Q000652:urine; D011692:Puromycin Aminonucleoside; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D018800:Thy-1 Antigens / Q000276:immunology
D000893:Anti-Inflammatory Agents; D003176:Complement C3; D007166:Immunosuppressive Agents; D018800:Thy-1 Antigens; D011692:Puromycin Aminonucleoside; D000068338:Everolimus; D020123:Sirolimus