[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

	Control	RK 2D	RK 2 Wk	RK 4Wk
Cortical Distal Tubular Cells	Focal apical	↑apical, mild diffuse	↑ extent, intensity	↑ extent, intensity
Medullary Tubular cells	Extensive, weak-moderate apical, often diffuse	No change	No change	No change
Glomeruli	Negative	Focal segmental capillary	Focal segmental in injured foci, capillaries	Focal segmental in injured foci, capillaries
Infarcted tissue	Not 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