Additive effect of PPAR-γ agonist and ARB in treatment of experimental IgA nephropathy.
Our recent in vitro study demonstrated peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist potentiated the anti-inflammatory effect of angiotensin receptor blocker (ARB) in tubular epithelial cell under milieu mimicking IgA nephropathy (IgAN). Here we studied the therapeutic effect of combining a PPAR-γ agonist, rosiglitazone (Ros), with an ARB, losartan (Los), in experimental IgAN induced in Lewis rats by oral and intravenous immunization with bovine gamma-globulin (BGG). The rats were randomly divided into six groups: control, IgAN, IgAN with unilateral nephrectomy (IgAN/1K), and IgAN/1K receiving Ros, Los, or Ros + Los. Medication was given 1 week after nephrectomy until killing. Rats developing IgAN had hematuria, mesangial hypercellularity with IgA deposition, glomerular damage, and tubulointerstitial infiltration of CD25+ leukocytes accompanied by increased renal expression of TGF-β, AngII receptor subtype-1 (ATR1) and ICAM-1. The renal histopathology, albuminuria, and renal expression of TGF-β, ATR1 and ICAM-1 worsened with unilateral nephrectomy. Ros or Los reduced the renal expression of PCNA, TGF-β, ATR1, and ICAM-1 in IgAN rats with nephrectomy. Despite no difference between rats treated with monotherapy, combined therapy offered additive effect with decreased renal expression of TGF-β, ATR1 and ICAM-1 and attenuation of renal injury. Our animal study suggests combined PPAR-γ agonist and ARB holds promise for future therapy for IgAN.
Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, 102 Pokfulam Road, Hong Kong. knlai@hkucc.hku.hk
Kar Neng
KN
Lai
Loretta Y Y
LY
Chan
Hong
H
Guo
Sydney C W
SC
Tang
Joseph C K
JC
Leung
D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure; D004359:Drug Therapy, Combination; D005922:Glomerulonephritis, IGA / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D050527:Mesangial Cells / Q000473:pathology; D009392:Nephrectomy; D047495:PPAR gamma / Q000819:agonists*; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D005719:gamma-Globulins
D047228:Angiotensin II Type 1 Receptor Blockers; D047495:PPAR gamma; D044140:Receptor, Angiotensin, Type 1; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D005719:gamma-Globulins; D000077154:Rosiglitazone; D018799:Intercellular Adhesion Molecule-1; D019808:Losartan