Promotion of cell proliferation by clusterin in the renal tissue repair phase after ischemia-reperfusion injury.
Renal repair begins soon after the kidney suffers ischemia-reperfusion injury (IRI); however, its molecular pathways are not fully understood. Clusterin (Clu) is a chaperone protein with cytoprotective functions in renal IRI. The aim of this study was to investigate the role of Clu in renal repair after IRI. IRI was induced in the left kidneys of wild-type (WT) C57BL/6J (B6) vs. Clu knockout (KO) B6 mice by clamping the renal pedicles for 28-45 min at the body temperature of 32°C. The renal repair was assessed by histology and confirmed by renal function. Gene expression was examined using PCR array. Here, we show that following IRI, renal tubular damage and Clu expression in WT kidneys were induced at day 1, reached the maximum at day 3, and significantly diminished at day 7 along with normal function, whereas the tubular damage in Clu KO kidneys steadily increased from initiation of insult to the end of the experiment, when renal failure occurred. Renal repair in WT kidneys was positively correlated with an increase in Ki67(+) proliferative tubular cells and survival from IRI. The functions of Clu in renal repair and renal tubular cell proliferation in cultures were associated with upregulation of a panel of genes that could positively regulate cell cycle progression and DNA damage repair, which might promote cell proliferation but not involve cell migration. In conclusion, these data suggest that Clu is required for renal tissue regeneration in the kidney repair phase after IRI, which is associated with promotion of tubular cell proliferation.
Dept. of Urologic Sciences, Univ. of British Columbia, VGH-Jack Bell Research Centre, 2660 Oak St., Vancouver, BC V6H 3Z6, Canada. caigan@mail.ubc.ca.
Christopher Y C
CY
Nguan
Qiunong
Q
Guan
Martin E
ME
Gleave
Caigan
C
Du
D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D051152:Clusterin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D019394:Ki-67 Antigen / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012038:Regeneration; D051437:Renal Insufficiency / Q000378:metabolism / Q000473:pathology; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection
D015415:Biomarkers; C495242:CLU protein, human; C495243:Clu protein, mouse; D051152:Clusterin; D019394:Ki-67 Antigen
AKI; cell proliferation; clusterin; kidney injury; kidney repair