[1545] Glycoportein nmb (Gpnmb) Is Upregulated with Injury in the Rat 5/6 Nephrectomy (Nx) Remnant Kidney (RK)

Y Wang, SG Adler, M Chamberlin, B Satirapoj, T Dai, J LaPage, CC Nast. Harbor-UCLA Medical Center, Torrance, CA; Cedars-Sinai Medical Center, Los Angeles, CA

Background: Gpnmb,a transmembrane glycoprotein, influences osteoblast differentiation, cell adhesion and cell migration. It is found in the renal tubulo-interstitium in an obstruction model and is increased in circulating monocytes from end stage renal disease patients. We identified markedly increased Gpnmb mRNA expression in 5/6 Nx RK using microarray with Affymetrix chip 230_2 and sought to confirm the expression and localization of Gpnmb in this model, as well as assess downstream activation of the cSrc-Syk signaling pathway, which regulates autophagy and resultant tubule cell survival or death.
Design: Rat 5/6 Nx RK and control kidneys (C) were stained by immunohistochemistry for Gpnmb, macrophages (F4/80), WT-1 and active phospho-Syk, and with lectins using Peanut agglutinin (PNA) and Phytogemagglutinin E (PHA-E) for tubular localization.
Results: Gpnmb staining in the cortex and medulla is detailed in the table below; there was no proximal tubular staining. At 2 and 4 wk, RK cortical distal and medullary tubules often were dilated and frequently contained Gpnmb+ cellular debris. In the 2 wk RK, phospho-Syk is upregulated in cortical distal tubular cells and occasionally co-localized with Gpnmb in the apical areas. Glomerular Gpnmb was found in capillary luminal macrophages and in areas of injury was associated with loss of WT-1 podocyte staining.

Gpnmb Kidney Staining
ControlRK 2DRK 2 WkRK 4Wk
Cortical Distal Tubular CellsFocal apical↑apical, mild diffuse↑ extent, intensity↑ extent, intensity
Medullary Tubular cellsExtensive, weak-moderate apical, often diffuseNo changeNo changeNo change
GlomeruliNegativeFocal segmental capillaryFocal segmental in injured foci, capillariesFocal segmental in injured foci, capillaries
Infarcted tissueNot present+ macrophages+ macrophages+ macrophages

Conclusions: Gpnmb is upregulated in viable renal tubular cells over time in the 5/6 Nx RK. The co-localization of Gpnmb with Syk phosphorylation provides evidence supporting the presence of an activated Gpnmb(ITAM)-cSrc-Syk signaling pathway during renal injury. The segmental loss of WT-1 glomerular staining associated with Gpnmb suggests there is a link to podocyte dedifferentiation. Gpnmb, a protein found to play a role in lysosomal trafficking and autophagy, also may play a pathogenetic role as renal injury advances, and may be a useful biomarker for progressive kidney injury.
Category: Kidney (does not include tumors)

Wednesday, March 24, 2010 1:00 PM

Poster Session VI # 243, Wednesday Afternoon


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