title: Chitinase-like protein Brp-39/YKL-40 modulates the renal response to ischemic injury and predicts delayed allograft function.
abstract: Kidney hypoperfusion during episodes of systemic hypotension or after surgical procurement for transplantation can lead to tubular cell death via necrosis and apoptosis, which trigger a series of responses that promote repair. The factors that contribute to the repair phase after kidney injury are not well understood. Using a urine proteomic screen in mice, we identified the macrophage-secreted chitinase-like protein Brp-39, the murine protein product of the chitinase 3-like 1 gene, as a critical component of this reparative response that serves to limit tubular cell apoptotic death via activation of Akt, improving animal survival after kidney ischemia/reperfusion. Examination of graded times of renal ischemia revealed a direct correlation between the degree of kidney injury and both Chi3l1/Brp-39 expression in the kidney and its levels in the urine. In samples collected from patients undergoing deceased-donor kidney transplantation, we found higher levels of the orthologous human protein, YKL-40, in urine and blood from allografts subjected to sufficient peri-transplant ischemia to cause delayed graft function than from allografts with slow or immediate graft function. Urinary levels of YKL-40 obtained within hours of transplant predicted the need for subsequent dialysis in these patients. In summary, these data suggest that Brp-39/YKL-40 is a sensor of the degree of injury, a critical mediator of the reparative response, and a possible biomarker to identify patients at greatest risk of sustained renal failure after transplantation.
authors.affiliation: Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Insa M
authors.initials: IM
authors.lastname: Schmidt
authors.forename: Isaac E
authors.initials: IE
authors.lastname: Hall
authors.forename: Sujata
authors.initials: S
authors.lastname: Kale
authors.forename: Sik
authors.initials: S
authors.lastname: Lee
authors.forename: Chuan-Hua
authors.initials: CH
authors.lastname: He
authors.forename: Yashang
authors.initials: Y
authors.lastname: Lee
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Chupp
authors.forename: Gilbert W
authors.initials: GW
authors.lastname: Moeckel
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
authors.forename: Chirag R
authors.initials: CR
authors.lastname: Parikh
authors.forename: Lloyd G
authors.initials: LG
authors.lastname: Cantley
mesh_terms: D054392:Adipokines / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002478:Cells, Cultured; D000071451:Chitinase-3-Like Protein 1; D051799:Delayed Graft Function / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology; D016030:Kidney Transplantation; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011237:Predictive Value of Tests; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D014184:Transplantation, Homologous
chemical_list: D054392:Adipokines; D015415:Biomarkers; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D037102:Lectins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C084533:CHI3L1 protein, human; C509289:Chil1 protein, mouse; C494918:AKT1 protein, human; C514862:Akt1 protein, mouse