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.

Association of Urinary Biomarkers of Inflammation, Injury, and Fibrosis with Renal Function Decline: The ACCORD Trial

“…YKL-40 is a product of the chitinase 3-like 1 gene and upregulated in kidney macrophages after ischemia-reperfusion injury (39). In addition, in AKI, elevated urinary levels of YKL-40 were associated with adverse outcomes, including renal function worsening and in-hospital death (13).…”

Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations

“…Mmp8 contributes to the resolution of inflammation, 44 while Mmp9 regulates re-epithelialization and collagen fibril formation during wound repair. 45 Chi3l1 encodes a protein secreted by macrophages that mediates kidney repair by limiting tubular cell death, 46 which may explain the increased cell death with c-fms inhibitor treatment. Collectively, these data clearly indicate the Ly6C int subset plays a paracrine role in repair of the tubular epithelium.…”

Macrophages in Kidney Injury, Inflammation, and Fibrosis

“…However, increasing evidence shows that macrophages also play a reparative role during the course of disease (12,75,80,106,116). Macrophages actively participate in clearance of apoptotic and necrotic cells to resolve injury and in remodeling of matrix to restore tissue in acute and chronic kidney disease (34, 53,72,112,116). The diverse roles of macrophages, from inflammation and injury to tissue repair and remodeling, are not fully understood.…”

“…Lin found that macrophage-derived Wnt7b also plays a critical role in promoting kidney regeneration via epithelial cell-cycle progression and basement membrane repair after IRI (80). Reparative macrophages also secrete chitinase-like protein BRP-39, which has been shown to promote regeneration in kidney by limiting tubular apoptosis via activation of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling (112). Heme-oxygenase-1 (HO-1), a protective and anti-inflammatory enzyme, is upregulated in the kidney in response to IRI.…”