Wnt signaling regulates macula densa structure and function

Abstract

The macula densa (MD), a plaque of 15–20 specialized cells, sits at the vascular pole of the glomerulus and plays a critical role in maintaining renal blood flow and glomerular filtration rate via tubuloglomerular feedback. Changes in renin state of the juxtaglomerular apparatus are known to be associated with alterations in MD cell morphology, although the underlying mechanism and importance of this phenomenon have been elusive. The canonical Wnt‐β catenin signaling pathway is known to regulate several cellular processes including embryonic development, cell proliferation, differentiation and homoeostasis. Glycogen synthase kinase 3 beta (GSK3b), a serine/threonine kinase, is involved in the phosphorylation and subsequent destablization of β catenin; thus, GSK3b plays a critical role in regulating the Wnt‐β catenin pathway. Lithium is a commonly used inhibitor of GSK3b in the kidney. Given the importance of Wnt‐β catenin in maintaining epithelial cell structure, the present studies aimed to explore its role in regulating MD morphology and function. Wild‐type mice were treated with lithium chloride for 2 weeks (40 mmol/kg chow for 7 days, and 60 mmol LiCl/kg chow subsequently), followed by harvesting and histological analysis of the kidneys. Lithium treatment caused a significant increase in the number of proliferating MD cells as quantified by Ki67 and EdU staining. As compared to control mice, MD cell number in the plaque was higher in lithium‐treated groups with several hyperplastic MD plaques observed containing > 40 cells. MD nucleus‐to‐cell volume ratio was 30% higher after lithium treatment. Using a O‐propargyl‐puromycin incorporation‐based protein synthesis imaging assay, a 3‐fold increase in protein synthesis was observed in MD cells after lithium treatment. Identical MD cell morphological alterations were observed in the newly generated nNOS‐Ctnnb1(Ex3) mice, a Wnt gain‐of‐function genetic model, confirming MD cell Wnt specificity of lithium treatment. In summary, Wnt signaling is an important regulator of MD morphology and cell biology, which may be involved in traditional renin and hemodynamic and novel tissue remodeling functions of MD cells.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.