Amelioration of anti-Thy1-glomerulonephritis by PPAR-gamma agonism without increase of endothelial progenitor cell homing.
Impaired glomerular endothelial integrity is pivotal in various renal diseases and depends on both the degree of glomerular endothelial injury and the effectiveness of glomerular endothelial repair. Glomerular endothelial repair is, in part, mediated by bone marrow-derived endothelial progenitor cells. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists have therapeutic actions independent of their insulin-sensitizing effects, including enhancement of endothelial progenitor cell function and differentiation. We evaluated the effect of PPAR-gamma agonist rosiglitazone (4 mg.kg(-1).day(-1)) on the course of anti-Thy1-glomerulonephritis in rats. Rosiglitazone limited the development of proteinuria and prevented plasma urea elevation (8.1 +/- 0.4 vs. 12.5 +/- 1.1 mmol/l, P = 0.002). Histologically, inflammatory cell influx was not affected, but rosiglitazone-treated rats did show fewer microaneurysmatic glomeruli on day 7 (26 +/- 3 vs. 41 +/- 5%, P = 0.01) and reduced activation of matrix production with reduced renal cortical transforming growth factor-beta, plasminogen activator inhibitor type 1, and fibronectin-1 mRNA expression. However, bone marrow-derived endothelial cell glomerular incorporation was not enhanced (3.1 +/- 0.4 vs. 3.6 +/- 0.3 cells/glomerular cross section; P = 0.31). Rosiglitazone treatment in nonnephritic rats did not influence proteinuria, urea, or renal histology. In conclusion, treatment with PPAR-gamma agonist rosiglitazone ameliorates the course of experimental glomerulonephritis in a nondiabetic model, but not through enhancing incorporation of bone marrow-derived endothelial cells in the glomerulus.
Westerweel
Peter E
PE
Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
den Ouden
Krista
K
Nguyen
Tri Q
TQ
Goldschmeding
Roel
R
Joles
Jaap A
JA
Verhaar
Marianne C
MC
D000783:Aneurysm / Q000473:pathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000187:drug effects*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D015433:Glomerulonephritis, Membranous / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007518:Isoantibodies / Q000276:immunology; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D047495:PPAR gamma / Q000819:agonists*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011507:Proteinuria / Q000652:urine; D051381:Rats; D011914:Rats, Inbred BN; D000077154:Rosiglitazone; D013234:Stem Cells / Q000166:cytology*; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000235:genetics; D014508:Urea / Q000097:blood
D005353:Fibronectins; D007004:Hypoglycemic Agents; D007518:Isoantibodies; D008565:Membrane Proteins; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; C035678:anti-Thy antibody; C113267:nephrin; D000077154:Rosiglitazone; D014508:Urea