Studies on the inflammatory response in experimental acute pyelonephritis and its importance for the development of renal scarring

Abstract: Acute pyelonephritis especially in childhood is a serious and globally common bacterial infection. The infecting microorganism is often derived from the patient's own bowel flora and mainly affects the renal parenchyma and pelvis. If left untreated, acute pyelonephritis can lead to renal scarring and renal failure with a need for dialysis and/or renal replacement therapy. The aim of the present study was to investigate the inflammatory processes involved in acute pyelonephritis and scarring using a murine model system. Thus mice were transurethrally inoculated with E. coli (CFT 073) or as control with saline. Inoculation was followed by temporary obstruction of the urethra. The mRNA expression of pro-inflammatory (IL-1, IL-6, IFN-gamma and TNF-alpha and antiinflammatory (IL-4, IL-10, IL-12, TGF-beta) cytokines were compared in infected and control mice. These studies showed that an early and sustained up regulation of pro-inflammatory and down- regulating cytokines was observed both locally in the kidneys and systemically in the spleen of infected mice as well as in saline inoculated and obstructed mice, indicating an influence of the obstruction per se. In order to evaluate the effect of an angiotensin 11 type 1 receptor antagonist, losartan, the same experimental model was used. Mice treated with losartan showed a marked reduction of TGF-beta mRNA expression and protein secretion compared to saline treated controls. A 50% reduction in cortical scarring was also observed at 3 and 8 weeks compared to control mice, but this difference failed to attain statistical significance (P = 0.07). The importance of IL-6 in the inflammatory response and for bacterial clearance was further studied in a strain of IL-6 deficient mice. Significantly lower TGF-beta mRNA and protein levels were found in the kidneys of IL-6 deficient mice compared to their wild type counterparts with acute pyelonephritis. In vitro rIL-6 significantly increased TGF-beta production from splenocytes in E. coli infected IL-6 deficient mice. IL-6 deficient mice displayed more severe histo-pathological indices and retained viable bacteria in their kidneys longer than their wild type counterparts. E. coli infection proved to be more lethal in IL-6 deficient mice as well. High MIP-2 (the mouse equivalent of human IL-8), MCP-1 and RANTES mRNA expression and protein production were found early after bacterial inoculation followed by a gradual decrease in kidney sections and homogenates of mice with acute experimental pyelonephritis. In IL-10 deficient mice higher MIP-2 production was found in the kidneys than in the wild type counterparts. Stimulation of a human renal epithelial cell line and human primary mesangial cells with the same bacterial antigen led to a rapid increase in IL-8, MCP-1 and RANTES gene expression. Likewise a rapid release of IL-8 and MCP-1 was observed in both cell types, while RANTES release was delayed. Conclusions: Acute experimental E. coli pyelonephritis and obstruction per se are both associated with a rapid up-regulation of pro-inflammatory and modulating cytokine and chemokine mRNA expression, both locally and systemically. The angiotensin II type I receptor antagonist, losartan, attenuated TGF-beta and reduced cortical scarring. IL-6 upregulate TGF-beta and is important for bacterial clearance from infected kidneys and also for host survival.