Enhanced hyaluronan synthesis in the MRL-Fas(Ipr) kidney: Role of cytokines

Background/Aim: Pathological accumulation of the extracellular matrix compo nent hyaluronan (HA) occurs in the kidney cortex in immune-system mediated tissue injury. The purpose of the present study was to examine the pattern of HA deposition and the mechanisms of HA synthesis in the MRL-Fas(lpr) mou se model of lupus nephritis. Methods: Kidneys from normal and autoimmune mi ce were examined for HA content by immunofluorescence staining. Steady stat e mRNA levels for key enzymes involved in HA synthesis - uridine diphosphat e-glucose dehydrogenase (UDPGDH) and HA synthases (HAS) 1, 2 and 3 - were a ssessed by reverse-transcriptase polymerase chain reaction (RT-PCR). Using cultured mouse tubular epithelial cells, the regulation of the HA productio n in vitro in response to tumor necrosis factor alpha and interferon gamma was also examined. Results: By immunofluorescence staining, large amounts o f HA were detected in the cortical interstitium of MRL-Fas(lpr) mice with a utoimmune renal injury, but not in congenic MRL-++ mice. By RT-PCR the pres ence of transcripts for several genes involved in the synthesis of HA in no rmal and autoimmune kidneys could be demonstrated, including mRNA for UDPGD H and HAS1 and HAS2, but not for HAS3. Except for HAS2, steady state mRNA l evels for these enzymes did not correlate with disease activity. Analyzing a kidney tubular epithelial cell line in vitro, it was found that tumor nec rosis factor alpha and interferon gamma, and particularly the combination o f these two cytokines, markedly enhanced the synthesis of HA. The expressio n of HAS2 mRNA was also enhanced in response to cytokine treatment. Conclus ions: HA deposition is prominent in MRL-Fas(lpr) mice with renal disease an d could be mediated by local synthesis through HAS1 and HAS2. We hypothesiz e that the enhanced synthesis of HA could be promoted by proinflammatory cy tokines in vivo. The functional significance of HA accumulation in autoimmu ne renal injury remains to be determined.