Additive effect of PPAR-γ agonist and ARB in treatment of experimental IgA nephropathy

• Published in: Pediatric nephrology (Berlin, West) Vol. 26; no. 2; pp. 257 - 266
• Main Authors: Lai, Kar Neng, Chan, Loretta Y. Y., Guo, Hong, Tang, Sydney C. W., Leung, Joseph C. K.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.02.2011; Springer
• Subjects: Analysis of Variance; Angiotensin; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Animals; Antigen-antibody reactions; Blood Pressure; Bone morphogenetic proteins; Drug Therapy, Combination; gamma-Globulins; Glomerulonephritis, IGA - chemically induced; Glomerulonephritis, IGA - drug therapy; Glomerulonephritis, IGA - metabolism; Glomerulonephritis, IGA - pathology; Health aspects; Immunoglobulin A; Intercellular Adhesion Molecule-1 - metabolism; Kidney - metabolism; Kidney - pathology; Kidney diseases; Leukocytes, Mononuclear; Losartan - pharmacology; Losartan - therapeutic use; Medicine; Medicine & Public Health; Mesangial Cells - pathology; Nephrectomy; Nephrology; Original Article; Pediatrics; PPAR gamma - agonists; Proteinuria - metabolism; Rats; Rats, Inbred Lew; Receptor, Angiotensin, Type 1 - metabolism; Renin-Angiotensin System - drug effects; Thiazolidinediones - pharmacology; Thiazolidinediones - therapeutic use; Transforming Growth Factor beta - metabolism; Transforming growth factors; Urology; Peroxisome proliferator-activated receptor-γ agonist; IgA nephropathy; Angiotensin receptor blocker; Nephrectomy; Tubular atrophy
• ISSN: 0931-041X; 1432-198X
• DOI: 10.1007/s00467-010-1703-y

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.