Blockade of Angiotensin II with Losartan Attenuates Transforming Growth Factor-β1 Inducible Gene-h3 (βig-h3) Expression in a Model of Chronic Cyclosporine Nephrotoxicity

Abstract

Background: We recently demonstrated that upregulation of the transforming growth factor (TGF)-β1 inducible gene-h3 (βig-h3) is associated with tubulointerstitial fibrosis (TIF) in a rat model of chronic cyclosporine A (CsA) nephrotoxicity. This study investigated the association between βig-h3 expression and TIF during losartan treatment in this model. Methods: Adult Sprague-Dawley rats kept on a salt-depleted diet (0.05% sodium) were treated daily for 4 weeks with vehicle (olive oil, 1 ml/kg), CsA (15 mg/kg) or both CsA and losartan (10 mg/kg in drinking water). The effect of losartan on βig-h3 expression was evaluated using in situ hybridization, immunohistochemistry and immunoblotting. Histopathology, expressions of TGF-β1 and intrarenal angiotensin II were compared across treatment groups. Results: Concurrent administration of losartan significantly attenuated βig-h3 mRNA and protein expression within the tubulointerstitium of CsA-treated kidneys. This was accompanied by the retardation of TIF (18 ± 5 vs. 39 ± 5%, p < 0.01 vs. CsA) and the expression of TGF-β1 mRNA (336 ± 49 vs. 685 ± 63%, p < 0.01 vs. CsA) and the number of angiotensin II-positive glomeruli (18 ± 5 vs. 38 ± 6, p < 0.05 vs. CsA). Conclusion: Losartan is capable of abrogating the upregulation of TGF-β1 and βig-h3 expression, and this is associated with attenuated tubulointerstitial fibrosis in chronic CsA nephrotoxicity.

Attenuation of Interstitial Inflammation and Fibrosis by Recombinant Human Erythropoietin in Chronic Cyclosporine Nephropathy

“…It is well known that TGF-β1 is implicated in the fibrosis of chronic CsA nephropathy [10], and along with others we have delineated that βig-h3 expression serves as an index of TGF-β1 bioactivity [30, 31, 40]. In the present study, we found that rHuEPO decreased interstitial fibrosis, and this was paralleled with suppressed TGF-β1 and βig-h3 expression, and this suppression was more pronounced at 4 weeks.…”

“…For coloration, sections were incubated with a mixture of 0.05% 3,3′-diaminobenzidine containing 0.01% H 2 O 2 at room temperature until a brown color was visible, washed with TBS, counterstained with hematoxylin and examined under a light microscope. The procedure of immunostaining for ED-1 (Serotec Inc., UK), C-reactive protein (CRP, Sigma) , EPO, EPOR, proliferating cell nuclear antigen (PCNA, Dako A/S, Denmark), and TGF-β1-inducible gene-h3 (βig-h3) [30, 31] was similar to that for OPN. The number of PCNA-, ED-1-, and CRP-positive cells was autocounted using a digital camera-based image analyzer at twenty different fields in each section under ×200 magnification.…”

Calcineurin Inhibitor Nephrotoxicity

“…The effects of ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) on CNI nephrotoxicity have been studied extensively. In rats, it was shown that ACEIs and ARBs can prevent cyclosporineinduced interstitial fibrosis and improve renal function (145,(357)(358)(359). Also, in humans, ACE inhibition reduced CNI nephrotoxicity associated with cyclosporine use (360) and improved alterations of the cardiovascular system generally observed in renal transplant patients (361).…”

Renal Protective Role of Atrial Natriuretic Peptide in Acute Sodium Overload-Induced Inflammatory Response

“…Based on these observations, ANG II production has been regarded as a key event of inflammation in the heart, vessels and kidney, and therefore it has been considered as a therapeutic target [9]. In this way, inhibitors of ANG II synthesis and/or AT1 and AT2 receptor antagonists improved renal function [10]. …”