Enhanced hyaluronan synthesis in the MRL-Fas(lpr) kidney: role of cytokines.
OBJECTIVE
Pathological accumulation of the extracellular matrix component 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) mouse model of lupus nephritis.


METHODS
Kidneys from normal and autoimmune mice were examined for HA content by immunofluorescence staining. Steady state mRNA levels for key enzymes involved in HA synthesis - uridine diphosphate-glucose dehydrogenase (UDPGDH) and HA synthases (HAS) 1, 2 and 3 - were assessed by reverse-transcriptase polymerase chain reaction (RT-PCR). Using cultured mouse tubular epithelial cells, the regulation of the HA production in vitro in response to tumor necrosis factor alpha and interferon gamma was also examined.


RESULTS
By immunofluorescence staining, large amounts of HA were detected in the cortical interstitium of MRL-Fas(lpr) mice with autoimmune renal injury, but not in congenic MRL-++ mice. By RT-PCR the presence of transcripts for several genes involved in the synthesis of HA in normal and autoimmune kidneys could be demonstrated, including mRNA for UDPGDH and HAS1 and HAS2, but not for HAS3. Except for HAS2, steady state mRNA levels for these enzymes did not correlate with disease activity. Analyzing a kidney tubular epithelial cell line in vitro, it was found that tumor necrosis factor alpha and interferon gamma, and particularly the combination of these two cytokines, markedly enhanced the synthesis of HA. The expression of HAS2 mRNA was also enhanced in response to cytokine treatment.


CONCLUSIONS
HA deposition is prominent in MRL-Fas(lpr) mice with renal disease and could be mediated by local synthesis through HAS1 and HAS2. We hypothesize that the enhanced synthesis of HA could be promoted by proinflammatory cytokines in vivo. The functional significance of HA accumulation in autoimmune renal injury remains to be determined.
Feusi
E
E
Physiological Institute, University Zürich-Irchel, Zürich, Switzerland.
Sun
L
L
Sibalic
A
A
Beck-Schimmer
B
B
Oertli
B
B
Wüthrich
R P
RP
D000818:Animals; D002461:Cell Line, Transformed; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D004195:Disease Models, Animal; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008181:Lupus Nephritis / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D019463:Mice, Inbred MRL lpr; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014533:Uridine Diphosphate Glucose Dehydrogenase / Q000096:biosynthesis
D016207:Cytokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D006820:Hyaluronic Acid; D014533:Uridine Diphosphate Glucose Dehydrogenase; D014453:Glucuronosyltransferase