NF-kappaB and chemokine-cytokine expression in renal tubulointerstitium in experimental hyperoxaluria. Role of the renin-angiotensin system.
Recent evidence indicates that the renin-angiotensin system (RAS) seems to play a considerable role in the development of tubulointerstitial (TI) lesions caused by hyperoxaluria (Hox). The purpose of the present study was to evaluate the specific mechanism by which Hox involving RAS induces chemokine and cytokine expression and, therefore, renal TI damage in the ethylene-glycol (ETG) induced hyperoxaluric rat model. Sprague-Dawley rats, separated into five groups, received: G1 regular water, and G2, G3, G4 and G5 1% ETG (a precursor for oxalates) in their drinking water for 4 weeks. An angiotensin converting enzyme inhibitor, benazepril (BZ) 10 mg/kg/day, angiotensin II receptor antagonists, subtype 1 (AT1) losartan (LOS) 40 mg/kg/day and subtype 2 (AT2) PD 123,319 (PD) 10 mg/kg/day, were administered daily to G3, G4 and G5, respectively. At the end of the study, the inflammatory response to Hox was evaluated using anti-NF-kappaB (p50), anti-IL-6, anti-MCP-1; anti-RANTES and anti-ED1 (monocytes/macrophages) in each group. In spite of the same urine oxalate levels, rats belonging to the hyperoxaluric groups treated with either BZ or LOS showed significantly (P<0.01) less TI lesions together with a lower immunoexpression of inflammatory mediators when compared with untreated hyperoxaluric animals. NF-kappaB (p50) was increased in tubular cells in the ETG group (43.6+/-8.7 positive cells/mm(2)) and was significantly (P<0.01) reduced by LOS (11.2+/-4 positive cells/mm(2)) and even more by BZ (6.1+/-2.4 positive cells/mm(2)). There was a significant (P<0.01) correlation between NF-kappaB (p50) positive cells and ED1 cells in the ETG group (r=0.88) and in the ETG+LOS group (r=0.92). LOS showed better control on IL-6 and MCP-1 with respect to untreated rats, while BZ showed the best control on RANTES and ED1 cells in comparison with untreated animals. Renal function was significantly (P<0.01) better preserved in BZ and LOS treated groups compared to both untreated animals and rats with PD, as indicated by creatinine clearance values. These results suggest that Hox stimulates the NF-kappaB cascade and, therefore, induces the overexpression of inflammatory mediators like IL-6, MCP-1, and RANTES. This pathway seems to be mediated not only by AT1 but also by AT2 receptors of angiotensin II.
Toblli
Jorge Eduardo
JE
Laboratory of Experimental Medicine, Hospital Alemán, Av. Pueyrredon 1640, Buenos Aires 1118, Argentina. jtoblli@hospitalaleman.com
Cao
Gabriel
G
Casas
Gabriel
G
Stella
Inés
I
Inserra
Felipe
F
Angerosa
Margarita
M
D000818:Animals; D002129:Calcium Oxalate; D016207:Cytokines / Q000378:metabolism*; D015870:Gene Expression; D006959:Hyperoxaluria / Q000503:physiopathology*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009395:Nephritis, Interstitial / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000502:physiology*
D016207:Cytokines; D016328:NF-kappa B; D002129:Calcium Oxalate