Breast Regression Protein-39/Chitinase 3-Like 1 Promotes Renal Fibrosis after Kidney Injury <i>via</i> Activation of Myofibroblasts.

Abstract

The normal response to kidney injury includes a robust inflammatory infiltrate of PMNs and macrophages. We previously showed that the small secreted protein breast regression protein-39 (BRP-39), also known as chitinase 3-like 1 (CHI3L1) and encoded by the <i>Chi3l1</i> gene, is expressed at high levels by macrophages during the early stages of kidney repair and promotes tubular cell survival <i>via</i> IL-13 receptor <i>α</i>2 (IL13R<i>α</i>2)-mediated signaling. Here, we investigated the role of BRP-39 in profibrotic responses after AKI. In wild-type mice, failure to resolve tubular injury after unilateral ischemia-reperfusion injury (U-IRI) led to sustained low-level <i>Chi3l1</i> mRNA expression by renal cells and promoted macrophage persistence and severe interstitial fibrosis. Analysis of macrophages isolated from wild-type kidneys 14 days after U-IRI revealed high-level expression of the profibrotic BRP-39 receptor <i>Ptgdr2</i>/<i>Crth2</i> and expression of the profibrotic markers <i>Lgals3</i>, <i>Pdgfb</i>, <i>Egf</i>, and <i>Tgfb</i> In comparison, injured kidneys from mice lacking BRP-39 had significantly fewer macrophages, reduced expression of profibrotic growth factors, and decreased accumulation of extracellular matrix. BRP-39 depletion did not affect myofibroblast accumulation but did attenuate myofibroblast expression of <i>Col1a1</i>, <i>Col3a1</i>, and <i>Fn1</i> Together, these results identify BRP-39 as an important activator of macrophage-myofibroblast crosstalk and profibrotic signaling in the setting of maladaptive kidney repair.