Focal glomerulosclerosis in the remnant kidney model - An inflammatory disease mediated by cytokines

Abstract

Background. The mechanism of progression of established renal disease remains unclear. While a low protein diet slows this progression, the role of cytokines in this process has been little investigated. Methods. We investigated cytokine expression by Northern blot and immunohistochemistry in two groups of 5/6 nephrectomized rats (5/6 Nx) fed a normal (24%) or low (6%) protein diet and compared them with sham operated controls. Results. The rats on 6% protein diet had significantly less focal glomerulosclerosis (FGS) (17.4 ± 4.4 vs 27.4 ± 8.8%, P < 0.05) and global sclerosis (GGS) after 7 weeks (0.4 ± 0.8 vs 3.5 ± 2.1% of glomeruli P < 0.05). Both experimental groups showed three times control levels of MCP-1 expression after 2 weeks. However in the 5/6 Nx 6% protein group the expression decreased at 4 weeks (1.5 times controls) and reached control levels after 7 weeks. In contrast, the 5/6 Nx 24% protein group exhibited a further marked increase after 4 weeks (5.6 times controls) and was still two-fold higher after 7 weeks. TGF-β expression was modestly but consistently increased at all time points (120-160% of controls), with no difference between the two study groups. Neither IL-1β or TNF-α was detectable at any time. Immunohistochemistry demonstrated TGF-β intracellularly in distal tubular cells in both experimental and control animals, while MCP-1 protein was found in the area of FGS and in the apical pole of distal tubular cells in both experimental groups. Glomerular and interstitial ED1 positive cells were significantly increased after four weeks in the 5/6 Nx 24% protein group (P < 0.05). Conclusions. A 'mechanical' injury to the kidney clearly results in an inflammatory response associated with the upregulation of MCP-1. A low protein diet modulates the expression of MCP-1 and improves the morphological sequelae seen after renal ablation.