Inhibition of hyaluronan is protective against renal ischaemia-reperfusion injury.
BACKGROUND
Ischaemia-reperfusion injury (IRI) to the kidney is a complex pathophysiological process that leads to acute renal failure and chronic dysfunction in renal allografts. It was previously demonstrated that during IRI, hyaluronan (HA) accumulates in the cortical and external medullary interstitium along with an increased expression of its main receptor, CD44, on inflammatory and tubular cells. The HA-CD44 pair may be involved in persistent post-ischaemic inflammation. Thus, we sought to determine the role of HA in the pathophysiology of ischaemia-reperfusion (IR) by preventing its accumulation in post-ischaemic kidney.


METHODS
C57BL/6 mice received a diet containing 4-methylumbelliferone (4-MU), a potent HA synthesis inhibitor. At the end of the treatment, unilateral renal IR was induced and mice were euthanized 48 h or 30 days post-IR.


RESULTS
4-MU treatment for 14 weeks reduced the plasma HA level and intra-renal HA content at 48 h post-IR, as well as CD44 expression, creatininemia and histopathological lesions. Moreover, inflammation was significantly attenuated and proliferation was reduced in animals treated with 4-MU. In addition, 4-MU-treated mice had a significantly reduced expression of α-SMA and collagen types I and III, i.e. less renal fibrosis, 30 days after IR compared with untreated mice.


CONCLUSIONS
Our results demonstrate that HA plays a significant role in the pathogenesis of IRI, perhaps in part through reduced expression of CD44. The suppression of HA accumulation during IR may protect renal function against ischaemic insults.
Molecular Physiology Research Unit (URPHYM)-NARILIS, University of Namur, Namur, Belgium.
Vanessa
V
Colombaro
Anne-Emilie
AE
Declèves
Inès
I
Jadot
Virginie
V
Voisin
Laetitia
L
Giordano
Isabelle
I
Habsch
Denis
D
Nonclercq
Bruno
B
Flamion
Nathalie
N
Caron
D058186:Acute Kidney Injury / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D004195:Disease Models, Animal; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006923:Hymecromone / Q000494:pharmacology*; D007202:Indicators and Reagents / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control*; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000150:complications / Q000517:prevention & control*
D007202:Indicators and Reagents; D006923:Hymecromone; D006820:Hyaluronic Acid
acute kidney injury; fibrosis; hyaluronan; inflammation; ischaemia–reperfusion