Expression of gremlin, a bone morphogenetic protein antagonist, in glomerular crescents of pauci-immune glomerulonephritis

• Published in: Nephrology, dialysis, transplantation dialysis, transplantation, 2007-07, Vol.22 (7), p.1882-1890
• Main Authors: Mezzano, Sergio, Droguett, Alejandra, Eugenia Burgos, M., Aros, Claudio, Ardiles, Leopoldo, Flores, Claudio, Carpio, Daniel, Carvajal, Gisselle, Ruiz-Ortega, Marta, Egido, Jesús
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Blotting, Western; BMP-7 antagonist; Bone Morphogenetic Proteins - antagonists & inhibitors; Cell Proliferation; Cells, Cultured; crescentic glomerulonephritis; Emergency and intensive care: renal failure. Dialysis management; epithelial mesenchymal transition (EMT); Fibrosis; Glomerulonephritis; Glomerulonephritis - immunology; Glomerulonephritis - metabolism; Glomerulonephritis - pathology; gremlin; Histocytochemistry; Humans; Immunohistochemistry; In Situ Hybridization; Intensive care medicine; Intercellular Signaling Peptides and Proteins - biosynthesis; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Kidney Tubules - metabolism; Kidney Tubules - pathology; Medical sciences; Monocytes - drug effects; Monocytes - metabolism; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Pharmacology. Drug treatments; RNA, Messenger - metabolism; Smad; TGF-β; Tissue Distribution; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology; Urinary system
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfm145

Background. Recent evidence in vitro and in vivo suggests that gremlin, a bone morphogenetic protein antagonist, is participating in tubular epithelial mesenchymal transition (EMT) in diabetic nephropathy as a downstream mediator of TGF-β. Since EMT also occurs in parietal epithelial glomerular cells (PECs) leading to crescent formation, we hypothesized that gremlin could participate in this process. With this aim we studied its expression in 30 renal biopsies of patients with pauci-immune crescentic nephritis. Methods. Gremlin was detected by in situ hybridization (ISH) and immunohistochemistry (IMH) and TGF-β by ISH and Smads by southwestern histochemistry (SWH). Phosphorylated Smad2, CTGF, BMP-7, PCNA, α-SMA, synaptopodin, CD-68, and phenotypic markers of PECs (cytokeratin, E-cadherin), were detected by IMH. In cultured human monocytes, gremlin and CTGF induction by TGF-β was studied by western blot. Results. We observed strong expression of gremlin mRNA and protein in cellular and fibrocellular crescents corresponding to proliferating PECs and monocytes, in co-localization with TGF-β. A marked over-expression of gremlin was also observed in tubular and infiltrating interstitial cells, correlating with tubulointerstitial fibrosis (r = 0.59; P < 0.01). A nuclear Smad activation in the same tubular cells, that are expressing TGF-β and gremlin, was detected. In human cultured monocytes, TGF-β induced gremlin production while CTGF expression was not detected. Conclusion. We postulate that gremlin may play a role in the fibrous process in crescentic nephritis, both in glomerular crescentic and tubular epithelial cells. The co-localization of gremlin and TGF-β expression found in glomeruli and tubular cells suggest that gremlin may be important in mediating some of the pathological effects of TGF-β.