Genes Expressed by the Kidney, but Not by Bone Marrow-Derived Cells, Underlie the Genetic Predisposition to Progressive Glomerulosclerosis after Mesangial Injury

Abstract

Abstract. Progressive renal failure is accompanied by uncontrolled accumulation of extracellular matrix in glomeruli and tubulointerstitium, eventually resulting in glomerulosclerosis. Although glomerulosclerosis occurs secondary to various renal diseases, the fact that not all patients develop progressive glomerulosclerosis suggests that genetic factors may underlie the tendency to progress, or not to progress. Identified were two Lewis rat substrains with small genetic differences but with considerable difference in resolution of glomerulonephritis after anti-Thy-1 administration. In the Lewis/Møllegard rat strain, anti-Thy-1 glomerulonephritis spontaneously resolves within 4 wk. In contrast, Lewis/Maastricht rats develop progressive glomerulosclerosis after induction of this disease. The involvement of bone marrowderived cells and kidney cells in the development of glomerulosclerosis was determined. In the first study, exchange of bone marrow between these substrains did not affect the course of anti-Thy-1 nephritis. Lewis/Møllegard rats recovered rapidly, but Lewis/Maastricht rats showed progressive disease regardless of the genotype of the bone marrow they received. In the second study, kidneys were exchanged between the substrains. After transplantation, anti-Thy-1 nephritis was induced and glomerular damage assessed at day 21. Severe damage was observed in Lewis/Maastricht glomeruli independent of whether the kidney had been transplanted or not. Similarly, Lewis/Møllegard glomeruli, whether transplanted or not, revealed no residual histopathologic abnormalities. The inherited differences between the two substrains with regard to their insusceptibility to develop progressive glomerulosclerosis after mesangial injury are governed by genes expressed by the kidney, but not by bone marrow-derived cells.

Genes Expressed by Both Mesangial Cells and Bone Marrow–Derived Cells Underlie Genetic Susceptibility to Crescentic Glomerulonephritis in the Rat

“…This contrasts with experiments in the Thy-1 model of mesangial proliferative glomerulonephritis in rats using kidney transplants, which showed that influx of macrophages was entirely dependent on circulating cells (21). Conversely, in the same Thy-1 model, experiments that used two substrains of Lewis rat with different susceptibility to glomerulosclerosis showed that this susceptibility is governed by genes that are expressed by the kidney (22). As far as we are aware, our study is the first to show a naturally occurring genetic susceptibility to glomerular inflammation that is dependent on the kidney.…”

Alternatively spliced isoforms of fibronectin in immune‐mediated glomerulosclerosis: the role of TGFβ and IL‐4

“…After induction of αThy1 nephritis, proteinuria started to develop at day 3. Mesangial cell proliferation and mesangial matrix expansion were visible after 6 days, and mesangial sclerosis was observed at day 14 36. Induction of CSS has been shown to result in the development of membranous nephropathy 26.…”

Differentiating Glomerular Inflammation from Fibrosis in a Bone Marrow Chimera for Rat Anti-Glomerular Basement Membrane Glomerulonephritis

“…Thus, even molecular nature of inflammation is different between the two, this difference is still likely caused by the local glomerular cells. Several previous studies using BM transfer models also supported that glomerular cells may be a determining factor for glomerulosclerosis [8, 9]. As fibrosis in GN may be a physiological response to irreparable GBM damage and glomerular hemorrhage rather than being an overreaction of healing/repairing process, is it possible that fibrosis will eventually occur in LEW WKY rats?…”