Hematopoietic growth factor inducible neurokinin-1 (Gpnmb/Osteoactivin) is a biomarker of progressive renal injury across species

Abstract

We sought to find a urinary biomarker for chronic kidney disease and tested hematopoietic growth factor inducible neurokinin-1 (HGFIN, also known as Gpnmb/Osteoactivin) as it was found to be a kidney injury biomarker in microarray studies. Here, we studied whether HGFIN is a marker of kidney disease progression. Its increase in kidney disease was confirmed by real-time PCR after 5/6 nephrectomy, in streptozotocin-induced diabetes, and in patients with chronic kidney disease. In the remnant kidney, HGFIN mRNA increased over time reflecting lesion chronicity. HGFIN was identified in the infarct portion of the remnant kidney in infiltrating hematopoietic interstitial cells, and in distal nephron tubules of the viable remnant kidney expressed de novo with increasing time. In vitro, it localized to cytoplasmic vesicles and cell membranes. Epithelial cells lining distal tubules and sloughed luminal tubule cells of patients expressed HGFIN protein. The urine HGFIN-to-creatinine ratio increased over time after 5/6 nephrectomy; increased in patients with proteinuric and polycystic kidney disease; and remained detectable in urine after prolonged freezer storage. The urine HGFIN-to-creatinine ratio compared favorably with the urine neutrophil gelatinase-associated lipocalin (NGAL)-to-creatinine ratio (both measured by commercial enzyme-linked immunosorbent assays (ELISAs)), and correlated strongly with proteinuria, but weakly with estimated glomerular filtration rate and serum creatinine. Thus, HGFIN may be a biomarker of progressive kidney disease.

Glycoprotein non-metastatic b (GPNMB): A metastatic mediator and emerging therapeutic target in cancer

“…In models of cardiomyopathy, liver fibrosis, and kidney disease, increased GPNMB expression was observed in resident and infiltrating macrophages and is thought to serve as a compensatory response to promote tissue repair through autophagy and phagocytosis of cell debris 75,82–84. During tissue repair, GPNMB localizes to LC3-positive lysosomes, which form during autophagy, and mediates degradation of cellular debris by promoting the fusion of autophagosomes to lysosomes 82,84…”

“…During tissue repair, GPNMB localizes to LC3-positive lysosomes, which form during autophagy, and mediates degradation of cellular debris by promoting the fusion of autophagosomes to lysosomes 82,84…”

Expression and immunolocalization of Gpnmb, a glioma‐associated glycoprotein, in normal and inflamed central nervous systems of adult rats

“…The cytoplasmic domain of Gpnmb contains potential interaction sites for a number of signaling molecules, including cyclin, mitogen‐activated protein kinase, and glycogen synthase kinase‐3 (Selim 2009). Gpnmb is localized not only to the cell surface membrane, but also to endoplasmic reticulum microsomes in osteoblasts (Abdelmagid et al 2008), melanosomes in melanoma cells (Hoashi et al 2010), phagosomes in macrophages (Li et al 2010), and cytoplasmic vesicles in renal tubule‐derived MDCT cells (Patel–Chamberlin et al 2011). Thus, Gpnmb is considered to function as a cell surface receptor, cell adhesion molecule, melanosomal protein, or soluble ligand (Selim 2009).…”

“…In addition to tumor progression, Gpnmb is considered to function in non‐tumorous tissues. Its expression is upregulated in damaged skeletal muscles (Furochi et al 2007b), liver (Haralanova–Ilieva et al 2005), and kidneys (Nakamura et al 2007; Pahl et al 2010; Li et al 2010; Patel–Cahmberlin et al 2011), and fractured bones (Abdelmagid et al 2010). In vitro studies have shown that Gpnmb induces osteoblast and osteoclast differentiation (Selim et al 2003; Selim et al 2007; Abdelmagid et al 2008; Sheng et al 2008).…”

An Experimental Model Study: Histomorphological and Ultrastructural Renal Changes in 1/2-5/6 Nephrectomized and Diabetic Rats

“…Chamberlin et al observed an increase in hematopoietic growth factor inducible neurokinin (HGFIN, also known as Gpnmb / Osteoactivin) in 5/6 nephrectomized and streptozotocin-induced diabetic rats and in patients with chronic kidney disease with real-time PCR. 31 Uninephrectomized rats were made diabetic by streptozotocin by Komers et al and in this model they examined Rho-associated kinases (ROCK) and their effects on blood pressure of the kidney. 32 Similar to these models, we used a model, nephrectomy with diabetes, to examine the renal damage by histomorphometry and constituted a reference by comparing light microscopic and ultrastructural findings for advanced studies in the future.…”