Renal hyaluronan accumulation and hyaluronan synthase expression after ischaemia-reperfusion injury in the rat

Göransson, Viktoria; Johnsson, Cecilia; Jacobson, Annica; Heldin, Paraskevi; Hällgren, Roger; Hansell, Peter

doi:10.1093/ndt/gfh003

Cited by 51 publications

(44 citation statements)

References 19 publications

(35 reference statements)

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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: 74%

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

Schmidt

Overdier²,

Sun³

et al. 2016

Am J Respir Crit Care Med

130

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: 74%

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

Schmidt

Overdier²,

Sun³

et al. 2016

Am J Respir Crit Care Med

130

145

View full text Add to dashboard Cite

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“…HA in epithelia is restricted to regenerating and proliferating cells, and high levels of HA in simple epithelia acts as an indicator of pathological processes (Tammi et al 2008a). In renal tubular cells, there is normally no HA, but in many disease states and injuries, the HA content increases (Asselman et al , 2005Goransson et al 2004). HA content increases in many cancers that evolve from simple epithelia, like ovarian, colon, and breast cancers, as reviewed recently (Sironen et al 2011b;Tammi et al 2008b).…”

Section: Discussionmentioning

confidence: 99%

HAS3-induced accumulation of hyaluronan in 3D MDCK cultures results in mitotic spindle misorientation and disturbed organization of epithelium

Rilla

Pasonen‐Seppänen

Kärnä

et al. 2011

Histochem Cell Biol

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The amount of hyaluronan (HA) is low in simple epithelia under normal conditions, but during tumorigenesis, trauma or inflammation HA is increased on the epithelial cells and surrounding stroma. Excessive HA in epithelia is suggested to interfere with cell-cell adhesions, resulting in disruption of the epithelial barrier function. In addition, stimulated HA synthesis has been correlated with epithelial-to-mesenchymal transition and invasion of cancer cells. However, the effects of HA overload on normal epithelial morphogenesis have not been characterized in detail. Madin-Darby canine kidney (MDCK) cells form polarized epithelial cysts, when grown in a 3-dimensional (3D) matrix. These cells were used to investigate whether stimulated HA synthesis, induced by stable overexpression of GFP-HAS3, influences cell polarization and epithelial morphogenesis. GFP-HAS3 expression in polarized MDCK cells resulted in active HA secretion at apical and basolateral membrane domains. HA-deposits interfered with the formation of cell-cell junctions, resulting in impaired barrier function. In 3D cyst cultures, HA accumulated into apical lumina and was also secreted from the basal side. The HAS3-expressing cysts failed to form a single lumen and instead displayed multiple small lumina. This phenotype was correlated with aberrant mitotic spindle orientation in dividing cells. The results of this study indicate that excess pericellular HA disturbs the normal cell-cell and cell-ECM interactions in simple epithelia, leading to aberrant epithelial morphogenesis. The morphological abnormalities observed in 3D epithelial cultures upon stimulated HAS3 expression may be related to premalignant changes, including intraluminal invasion and deregulated epithelialization, probably mediated by the mitotic spindle orientation defects.

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“…We also quantitatively assessed mRNA levels of all three isoforms of hyaluronan synthase (HAS) reflecting hyaluronan biosynthesis (44). These proteins are endogenous ligands of TLRs and are released from damaged tissues (5,11,37). It has been previously demonstrated that TLRs, particularly TLR 4, mediate renal ischemia-reperfusion injury (11).…”

Section: Discussionmentioning

confidence: 99%

“…These proteins are endogenous ligands of TLRs and are released from damaged tissues (5,11,37). It has been previously demonstrated that TLRs, particularly TLR 4, mediate renal ischemia-reperfusion injury (11). TLRs are upregulated during hypoxia by mechanisms involving HIF-1␣ (16).…”

Section: Discussionmentioning

confidence: 99%

Morg1 heterozygous mice are protected from acute renal ischemia-reperfusion injury

Hammerschmidt

Loeffler

Wolf

2009

American Journal of Physiology-Renal Physiology

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Renal hyaluronan accumulation and hyaluronan synthase expression after ischaemia-reperfusion injury in the rat

Cited by 51 publications

References 19 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

HAS3-induced accumulation of hyaluronan in 3D MDCK cultures results in mitotic spindle misorientation and disturbed organization of epithelium

Morg1 heterozygous mice are protected from acute renal ischemia-reperfusion injury

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