Breast Regression Protein–39/Chitinase 3–Like 1 Promotes Renal Fibrosis after Kidney Injury via 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 gene, is expressed at high levels by macrophages during the early stages of kidney repair and promotes tubular cell survival IL-13 receptor 2 (IL13R2)-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 mRNA expressionby 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 / and expression of the profibrotic markers ,, , and 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 ,, and Together, these results identify BRP-39 as an important activator of macrophage-myofibroblast crosstalk and profibrotic signaling in the setting of maladaptive kidney repair.

Development of a 2-dimensional atlas of the human kidney with imaging mass cytometry

“…The renal interstitium includes the vascular and stromal cell populations that surround and support the tubular epithelium. The interstitium also includes the collagenous matrix surrounding the tubules, which is believed to undergo extensive changes during acute and chronic disease (27). Interstitial markers analyzed in this experiment include collagen IV, a marker of glomerular and tubular basement membrane, as well as α-smooth muscle actin (α-SMA) and vimentin, which mark stromal cells including fibroblasts, myofibroblasts, and pericytes ( Figure 1, E and G, and Figure 3).…”

Kidney single-cell atlas reveals myeloid heterogeneity in progression and regression of kidney disease

“…The innate immune system has been implicated in both progression and regression of fibrosis in multiple organs including the kidney (11)(12)(13)(14)(15). Recruitment of pro-inflammatory monocytes (16,17) to the injured kidney via CCL1-CCR2 signalling (18,19) may exacerbate tissue damage through the release of pro-inflammatory factors and by activating myofibroblasts.…”

The global proteome and phosphoproteome landscape of sepsis-induced kidney injury

“…Chil3 has been reported as a biomarker for skin wound infection 96 , cardiovascular disease and diabetes 97 , and cancer 98 . A handful of studies have shown that Chil3 has critical functional relevance to kidney ischemic injury 99 and renal fibrosis 100 . There is also evidence showing its potential in predicting the onset and recovery of acute kidney injuries 75,100,101 .…”

“…A handful of studies have shown that Chil3 has critical functional relevance to kidney ischemic injury 99 and renal fibrosis 100 . There is also evidence showing its potential in predicting the onset and recovery of acute kidney injuries 75,100,101 . However, the majority of these studies investigated chitinase secretion into the urine and used the urinary form as an indicator of disease status, which might be complicated by other non-kidney diseases such as urothelial carcinoma 102 .…”