Colchicine Suppresses Osteopontin Expression and Inflammatory Cell Infiltration in Chronic Cyclosporine Nephrotoxicity

Abstract

Background: Colchicine (Col) is beneficial to renal injury because of its anti-inflammatory effect, but its mechanism has yet to be elucidated. The present study was designed to evaluate the inhibitory effects of colchicine on osteopontin (OPN) expression and the macrophage accumulation in chronic cyclosporine (CsA) nephrotoxicity in rats. Methods: Male adult Sprague-Dawley rats on a low salt diet (LSD, 0.05% sodium) were treated daily with Col (30 µg/kg), CsA (15 mg/kg), and both CsA and colchicine or vehicle (olive oil 1 ml/kg) for 4 weeks. The effects of colchicine on chronic CsA nephrotoxicity were evaluated by examining renal function, histopathology, and ED-1 positive cells. The expressions of OPN mRNA and protein were estimated respectively by Northern blot and immunohistochemistry. Results: Compared with vehicle-treated rats, CsA-treated rats showed an increase in serum creatinine, a decline in creatinine clearance rate, and tubulointerstitial fibrosis (all p < 0.01). Concomitant administration of colchicine reversed all of the above parameters (all p < 0.01). Of note, the upregulated expression of osteopontin mRNA and protein seen in CsA-treated rats was significantly decreased after colchicine treatment. Furthermore, the expression of osteopontin mRNA was strongly correlated with the number of ED-1 positive cells (r = 0.712, p < 0.001) and the tubulointerstitial fibrosis score (r = 0.586, p = 0.007). Conclusion: Colchicine is capable of abrogating the upregulation of chemotactic OPN expression and macrophage influx, and this is associated with improved renal tubulointerstitial fibrosis in chronic CsA nephrotoxicity.

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

“…Others and we have demonstrated that overexpression of OPN is closely associated with macrophage infiltration as well as TIF in chronic CsA nephropathy [27, 28, 38]. Furthermore,mice lacking OPN (OPN–/–) showed less chronic CsA nephropathy than OPN wild-type (OPN+/+) mice [39], indicating a role for OPN in chronic CsA nephropathy.…”

“…Tubulointerstitial inflammation is critical in the development of chronic CsA nephropathy, and several proinflammatory mediators are involved in this process [11, 27, 28]. In this study, we evaluated infiltration of macrophages and two potential proinflammatory mediators (OPN and CRP) as markers of CsA-induced inflammation.…”

“…Probes were precipitated and incorporation of DIG was determined by dot blotting. Northern blotting was performed as previously described by our laboratory [26,27,28] and others [29]. Briefly, kidney cortex was homogenized.…”

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

“…In this context, this study aimed to investigate the effect of losartan on βig-h3 expression and its relation to TIF in a well-established rat model of chronic CsA nephrotoxicity [7, 8, 9, 10, 11, 12, 13, 20, 21, 22]. …”

Colchicine in Renal Medicine: New Virtues of an Ancient Friend

“…Colchicine inhibits lymphocyte proliferation and function [21,22] . In the rat chronic cyclosporine (CsA) nephrotoxicity model, colchicine prevented macrophage influx and renal tubulointerstitial fibrosis [23] . Similarly, colchicine prevented macrophage infil- Experimental and clinical studies of colchicine in the renal disease processes with prominent fibrosis or in fibrotic disorders in which kidney is involved collaterally Reference Study design and setting…”