Upregulated mTOR Pathway in Primary Crescentic Glomerulonephritis
Ping L Zhang, Francis Dumber, Michele T Rooney, Wei Li. William Beaumont Hospital, Royal Oak, MI
Background: The current treatment for crescentic glomerulonephritis (CGN) is limited. The mammalian target of rapamycin (mTOR) pathway, as a major branch of growth factor-related cellular proliferation pathways, is involved in the metabolism of glomerular visceral and parietal epithelium of glomeruli in animal studies. We therefore investigated the expression of phosphorylated (p)-mTOR (activated form) and its major downstream signal p-p70S6K in CGN.
Design: The study materials included 15 unremarkable control kidney sections (removed for renal tumors), 15 samples with focal segmental glomerulosclerosis, 16 with immune complex mediated glomerulopathy (membranous GN, lupus nephritis and membranoproliferative GN) and 25 primary CGN (either ANCA associated pauci-immune type or anti-GBM type). All sections were stained for p-mTOR (Ser 2448) and p-p70S6K (Thr 389) (from Cell Signaling Technology), using a Dako Autostainer.
Results: p-mTOR and p-p70S6K demonstrated significant upregulation in renal tubules, parietal and visceral epithelium of glomeruli in all three disease groups, comparing to the control group. Serum creatinine levels in the crescentic group was significantly higher than in the other three groups. In the crescentic group, mean crescentic involvement in glomeruli was 53.3%. A total of 22 out of 25 (88%) CGN showed upregulated nuclear staining of p-p70S6K and cytoplasmic staining of p-mTOR in the crescentic epithelium (panels B and D; arrows point to crescents), when compared to controls (panels A and C).
The 3 negative stained cases included 1 with fibrocellular crescents, 1 without crescents in deep sections, and 1 without glomeruli in the deep section. On PAS stained sections, upregulated unclear p-p70S6K was further confirmed in the cellular crescents.
Conclusions: In renal biopsies with various kidney diseases, a prominent upregulation of mTOR pathway signals in glomerular visceral/parietal epithelium and renal tubular epithelium was observed in all glomerulonephritis cases, indicating an increased proliferative activity in many types of glomerulonephritis. Upregulated p-mTOR and p-p70S6K in the crescentic components raise the possibility of using mTOR inhibitors as an alterative treatment in CGN.
Category: Kidney (does not include tumors)
Wednesday, March 21, 2012 1:00 PM
Poster Session VI # 282, Wednesday Afternoon