Colchicine attenuates renal injury in a model of hypertensive chronic kidney disease

Abstract

Hypertension is a risk factor for chronic kidney disease, particularly when associated with impaired renal autoregulation and thereby increased intraglomerular pressure (Pgc). Elevated Pgc can be modeled in vitro by exposing glomerular mesangial cells to mechanical strain. We previously showed that RhoA mediates strain-induced matrix production. Here, we show that RhoA activation is dependent on an intact microtubule network. Upregulation of the profibrotic cytokine connective tissue growth factor (CTGF) by mechanical strain is dependent on RhoA activation and inhibited by microtubule disruption. We tested the effects of the microtubule depolymerizing agent colchicine in 5/6 nephrectomized rats, a model of chronic kidney disease driven by elevated Pgc. Colchicine inhibited glomerular RhoA activation and attenuated both glomerular sclerosis and interstitial fibrosis without affecting systemic blood pressure. Upregulation of the matrix proteins collagen I and fibronectin, as well as CTGF, was attenuated by colchicine. Activity of the profibrotic cytokine TGF-β, as assessed by Smad3 phosphorylation, was also inhibited by colchicine. Microtubule disruption significantly decreased renal infiltration of lymphocytes and macrophages. Our studies thus indicate that colchicine modifies hypertensive renal fibrosis. Its protective effects are likely mediated by inhibition of RhoA signaling and renal infiltration of inflammatory cells. Already well-established in clinical practice for other indications, prevention of hypertension-associated renal fibrosis may represent a new potential use for colchicine.

Colchicine—Update on mechanisms of action and therapeutic uses

“…In a rat model of cyclosporine nephrotoxicity, colchicine inhibited tubulointerstitial fibrosis by stimulating B-cell lymphoma 2 (Bcl-2) expression and suppression of caspase-3 and thereby suppressed renal cell apoptosis [37]. In a rat model of hypertensive chronic kidney disease, colchicine inhibited renal fibrosis via inhibition of RhoA signalling and infiltration of inflammatory cells [38]. In a rat model, colchicine inhibited liver fibrosis by inhibiting the activation of hepatic stellate cells and induced stellate cell apoptosis [39].…”

Colchicine in Renal Medicine: New Virtues of an Ancient Friend

“…Colchicine also reduced the pro-fibrotic cytokines TGF-β activity and connective tissue growth factor and the upregulation of ECM proteins, collagen I, and fibronectin. Besides this, colchicine decreased the renal infiltration of lymphocytes and macrophages [55] . RhoA/Rho-kinase signaling is dependent on an intact microtubule network [56] and RhoA kinase inhibition by colchicine could underlie the nephroprotective effect in renal mass reduction [57] .…”

The cytoskeleton as a novel target for treatment of renal fibrosis

“…Colchicine, an inhibitor of microtubule polymerization (Leung et al, 2015), decreases RhoA activation in the 5/6 nephrectomy model (Guan et al, 2013). Importantly, colchicine decreased both glomerulosclerosis and interstitial fibrosis, and decreased the upregulation of collagen I, fibronectin and CTGF.…”