Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction.
Tubulointerstitial fibrosis is a hallmark of chronic progressive kidney disease leading to end-stage renal failure. An endogenous product of heme oxygenase activity, carbon monoxide (CO), has been shown to exert cytoprotection against tissue injury. Here, we explored the effects of exogenous administration of low-dose CO in an in vivo model of renal fibrosis induced by unilateral ureteral obstruction (UUO) and examined whether CO can protect against kidney injury. UUO in mice leads to increased extracellular matrix (ECM) deposition and tubulointerstitial fibrosis within 4 to 7 days. Kidneys of mice exposed to low-dose CO, however, had markedly reduced ECM deposition after UUO. Moreover, low-dose CO treatment inhibited the induction of alpha-smooth muscle actin (alpha-SMA) and major ECM proteins, type 1 collagen and fibronectin, in kidneys after UUO. In contrast, these anti-fibrotic effects of CO treatment were abrogated in mice carrying null mutation of Mkk3, suggesting involvement of the MKK3 signaling pathway in mediating the CO effects. Additionally, in vitro CO exposure markedly inhibited TGF-beta(1)-induced expression of alpha-SMA, collagen, and fibronectin in renal proximal tubular epithelial cells. Our findings suggest that low-dose CO exerts protective effects, via the MKK3 pathway, to inhibit development of renal fibrosis in obstructive nephropathy.
Wang
Lin
L
Department of Medicine, Renal Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Lee
Ji-Yang Sophie
JY
Kwak
Joon Hyeok
JH
He
Yanjuan
Y
Kim
Sung Il
SI
Choi
Mary E
ME
D000199:Actins / Q000378:metabolism; D000280:Administration, Inhalation; D000818:Animals; D000963:Antimetabolites / Q000008:administration & dosage / Q000627:therapeutic use*; D002248:Carbon Monoxide / Q000008:administration & dosage / Q000627:therapeutic use*; D024042:Collagen Type I / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000209:etiology / Q000517:prevention & control; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications*
D000199:Actins; D000963:Antimetabolites; D002248:Carbon Monoxide; D024042:Collagen Type I; D005353:Fibronectins; D048371:MAP Kinase Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016212:Transforming Growth Factor beta; C498862:Acta2 protein, rat