Colchicine attenuates renal injury in a model of hypertensive chronic kidney disease.
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.
St. Joseph's Hospital, 50 Charlton Ave East, Rm. T3311, Hamilton, ON, L8N 4A6, Canada. krepinj@mcmaster.ca.
Tianxiu
T
Guan
Bo
B
Gao
Guang
G
Chen
Xing
X
Chen
Melissa
M
Janssen
Lalita
L
Uttarwar
Alistair J
AJ
Ingram
Joan C
JC
Krepinsky
D000818:Animals; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology*; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics; D019610:Cytoprotection; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008870:Microtubules / Q000378:metabolism; D009392:Nephrectomy; D009393:Nephritis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051900:Smad3 Protein / Q000378:metabolism; D013314:Stress, Mechanical; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D024042:Collagen Type I; D005353:Fibronectins; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D020742:rhoA GTP-Binding Protein; D003078:Colchicine
CTGF; RhoA; TGF-β; glomerular sclerosis; hypertensive nephropathy; microtubules