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: Insa M Schmidt, Isaac E Hall, Sujata Kale, Sik Lee, Chuan-Hua He, Yashang Lee, Geoffrey L Chupp, Gilbert W Moeckel, Chun Geun Lee, Jack A Elias, Chirag R Parikh, Lloyd G Cantley
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 24 Issue 2 Pg. 309-19 (Feb 2013) ISSN: 1533-3450 [Electronic] United States
• PMID: 23291472 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adipokines
• Biomarkers
• CHI3L1 protein, human
• Chil1 protein, mouse
• Chitinase-3-Like Protein 1
• Glycoproteins
• Lectins
• AKT1 protein, human
• Akt1 protein, mouse
• Proto-Oncogene Proteins c-akt

Topics

• Adipokines (genetics, metabolism)
• Animals
• Apoptosis (physiology)
• Biomarkers (blood, urine)
• Cells, Cultured
• Chitinase-3-Like Protein 1
• Delayed Graft Function (metabolism, mortality, physiopathology)
• Disease Models, Animal
• Epithelial Cells (cytology)
• Glycoproteins (genetics, metabolism)
• Humans
• Kidney (cytology)
• Kidney Transplantation
• Lectins (genetics, metabolism)
• Macrophages (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Phosphatidylinositol 3-Kinases (metabolism)
• Predictive Value of Tests
• Proto-Oncogene Proteins c-akt (metabolism)
• Reperfusion Injury (metabolism, mortality, physiopathology)
• Signal Transduction (physiology)
• Transplantation, Homologous