The role of Macrophage Delivered WNT Signaling in kidney injury and repair

University Of Washington, Seattle WA

Investigators

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Abstract

DESCRIPTION (provided by applicant): Chronic kidney disease is a public health epidemic affecting millions. The toll to health care, our communities and to individuals is profound. Chronic kidney disease and is characterized by chronic inflammation, parenchymal cell loss and fibrosis. However the kidney when injured has enormous capacity for recovery. Understanding the mechanisms of normal recovery and how they differ from progressive inflammation in the kidney will lead to new therapies. We have been studying the role of macrophages, cells of the immune system recruited to the kidney, in regulating the normal repair process in the kidney and in directing the development of fibrosis, which is a harbinger of kidney failure. We have discovered that the Canonical WNT cell-to-cell signaling pathway, that regulates cell survival, differentiation, migration, proliferation and apoptosis, once thought to be restricted to paracrine cell communications of embryonic development and cancer, is active during kidney repair and also during kidney fibrosis. Our central hypothesis supported by extensive preliminary data is that inflammatory macrophages in the kidney release soluble ligands (WNTs) that signal via WNT receptors on paracrine cells and that this signaling plays an important role in mediating kidney repair. However when injury is persistent, WNT signaling from inflammatory macrophages supports the increase in interstitial fibroblasts and directs generation of scar tissue. In AIM 1 we will focus on normal kidney repair following injury. We will examine the precise role of inflammatory macrophages and dissect a supporting role from epithelial cells in delivering WNT signals to neighboring cells of the kidney. We will use genetic approaches in the mouse to study: the effect of conditional ablation of macrophages in vivo on WNT signaling; the importance of WNT receptors Frizzled-4, Lrp-5 and Lrp-6 in kidney repair; and the role of macrophage Wnt-7b or the Wnt ligand release protein Wntless in vivo, in repair. We will administer soluble modulators of WNT signaling to affect repair of the kidney. In AIM 2 we will focus Macrophage delivered WNT signaling on the progression of fibrosis in the kidney. Using genetic approaches in the mouse we will study the role of fibroblast WNT receptor Frizzled-7; the macrophage Wnt ligand release protein Wntless; and the transcriptional regulator ¿-catenin in fibroblasts, on fibrosis progression in vivo. We will test the impact of soluble WNT modulators including Dickkopf-1 and -2 on fibrosis progression. Relevance: The overall purpose of these studies is to determine the roles of Canonical WNT signaling from macrophages, particularly to epithelial cells in normal kidney repair, but also to fibroblasts in the development of fibrosis. By understanding the mechanisms by which macrophages regulate injury and repair in the kidney we will develop new therapeutic paradigms that support normal repair, and counteract fibrosis in humans.