Synthesis and fragmentation of hyaluronan in renal ischaemia

Declèves, Anne‐Emilie; Caron, Nathalie; Voisin, Virginie; Legrand, Alexandre; Bouby, Nadine; Kultti, Anne; Tammi, Markku; Flamion, Bruno

doi:10.1093/ndt/gfs098

Cited by 31 publications

(29 citation statements)

References 30 publications

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“…HA has been implicated in several renal diseases, including renal ischemiareperfusion injury (18)(19)(20). We observed that patients with septic shock had a significant increase in urine HA, which was predictive of renal dysfunction and (on unadjusted analyses) in-hospital mortality.…”

Section: Discussionmentioning

confidence: 70%

Urinary Glycosaminoglycans Predict Outcomes in Septic Shock and Acute Respiratory Distress Syndrome

Schmidt

Overdier²,

Sun³

et al. 2016

Am J Respir Crit Care Med

133

145

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Rationale: Degradation of the endothelial glycocalyx, a glycosaminoglycan (GAG)-rich layer lining the vascular lumen, is associated with the onset of kidney injury in animal models of critical illness. It is unclear if similar pathogenic degradation occurs in critically ill patients.Objectives: To determine if urinary indices of GAG fragmentation are associated with outcomes in patients with critical illnesses such as septic shock or acute respiratory distress syndrome (ARDS).Methods: We prospectively collected urine from 30 patients within 24 hours of admission to the Denver Health Medical Intensive Care Unit (ICU) for septic shock. As a nonseptic ICU control, we collected urine from 25 surgical ICU patients admitted for trauma. As a medical ICU validation cohort, we obtained serially collected urine samples from 70 patients with ARDS. We performed mass spectrometry on urine samples to determine GAG (heparan sulfate, chondroitin sulfate, and hyaluronic acid) concentrations as well as patterns of heparan sulfate/chondroitin sulfate disaccharide sulfation. We compared these indices to measurements obtained using dimethylmethylene blue, an inexpensive, colorimetric urinary assay of sulfated GAGs. Measurements and Main Results:In septic shock, indices of GAG fragmentation correlated with both the development of renal dysfunction over the 72 hours after urine collection and with hospital mortality. This association remained after controlling for severity of illness and was similarly observed using the inexpensive dimethylmethylene blue assay. These predictive findings were corroborated using urine samples previously collected at three consecutive time points from patients with ARDS.Conclusions: Early indices of urinary GAG fragmentation predict acute kidney injury and in-hospital mortality in patients with septic shock or ARDS.Clinical trial registered with www.clinicaltrials.gov (NCT01900275).

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Section: Discussionmentioning

confidence: 70%

Urinary Glycosaminoglycans Predict Outcomes in Septic Shock and Acute Respiratory Distress Syndrome

Schmidt

Overdier²,

Sun³

et al. 2016

Am J Respir Crit Care Med

133

145

View full text Add to dashboard Cite

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“…Previous investigators have described a correlation between functional renal impairment and HA content in rat IRI. 14,19 In a recent study in mice, we have shown that suppression of HA accumulation during IRI using the HA synthase inhibitor 4-methylumbelliferone is protective against ischemic insults. 15 Now we show that enhancement of HA accumulation through a lack of renal hyaluronidase activity aggravates IRI.…”

Section: Discussionmentioning

confidence: 99%

“…HYAL1 and HYAL2 are the major hyaluronidases in somatic tissues, whereas HA synthesis is achieved by three HA synthases. 7 Declèves et al 14 have demonstrated that HA accumulation in the post-ischemic kidney is related to temporal changes in the level of expression of its metabolic enzymes: Hyal1 and Hyal2 mRNA expression are repressed during the first 24 h post-IR, whereas Has1 is upregulated, thereby promoting the accumulation of HA. Has2 mRNA expression is markedly increased 7 and 14 days after IR, whereas Has1 mRNA expression decreases at this time point.…”

mentioning

confidence: 99%

Lack of hyaluronidases exacerbates renal post-ischemic injury, inflammation, and fibrosis

Colombaro

Jadot

Declèves

et al. 2015

Kidney International

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Renal ischemia-reperfusion injury (IRI) is a pathological process that may lead to acute renal failure and chronic dysfunction in renal allografts. During IRI, hyaluronan (HA) accumulates in the kidney, but suppression of HA accumulation during IRI protects the kidney from ischemic insults. Here we tested whether Hyal1-/- and Hyal2-/- mice display exacerbated renal damage following unilateral IRI due to a higher HA accumulation in the post-ischemic kidney compared with that in the kidney of wild-type mice. Two days after IRI in male mice there was accumulation of HA and CD44 in the kidney, marked tubular damage, infiltration, and increase creatininemia in wild-type mice. Knockout mice exhibited higher amounts of HA and higher creatininemia. Seven days after injury, wild-type mice had a significant decrease in renal damage, but knockout mice still displayed exacerbated inflammation. HA and CD44 together with α-smooth muscle actin and collagen types I and III expression were increased in knockout compared with wild-type mice 30 days after IRI. Thus, both HA-degrading enzymes seem to be protective against IRI most likely by reducing HA accumulation in the post-ischemic kidney and decreasing the inflammatory processes. Deficiency in either HYAL1 or HYAL2 leads to enhanced HA accumulation in the post-ischemic kidney and consequently worsened inflammatory response, increased tubular damage, and fibrosis.

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“…A stimulus often increases the expression of two (48) or all three of the HASs (47,49). Induction of the HAS isoforms occurs at different time points following a stimulus, lasts for different periods of time, and is mediated by different signaling pathways (49).…”

Section: Discussionmentioning

confidence: 99%

Fluorescence Resonance Energy Transfer (FRET) and Proximity Ligation Assays Reveal Functionally Relevant Homo- and Heteromeric Complexes among Hyaluronan Synthases HAS1, HAS2, and HAS3

Bart

Vico

Hassinen

et al. 2015

Journal of Biological Chemistry

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Synthesis and fragmentation of hyaluronan in renal ischaemia

Cited by 31 publications

References 30 publications

Urinary Glycosaminoglycans Predict Outcomes in Septic Shock and Acute Respiratory Distress Syndrome

Urinary Glycosaminoglycans Predict Outcomes in Septic Shock and Acute Respiratory Distress Syndrome

Lack of hyaluronidases exacerbates renal post-ischemic injury, inflammation, and fibrosis

Fluorescence Resonance Energy Transfer (FRET) and Proximity Ligation Assays Reveal Functionally Relevant Homo- and Heteromeric Complexes among Hyaluronan Synthases HAS1, HAS2, and HAS3

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