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Hyaluronan Production by Renomedullary Interstitial Cells: Influence of Endothelin, Angiotensin II and Vasopressin
The Swedish Red Cross University College, Department of Health Sciences. Uppsala universitet, Institutionen för medicinsk cellbiologi.ORCID iD: 0000-0003-4092-2854
Uppsala universitet, Institutionen för medicinsk cellbiologi. (Department of Medical and Health Sciences)
Hoshi University, Tokyo, Japan . (Faculty of Pharmaceutical Sciences)
Hoshi University, Tokyo, Japan . (Faculty of Pharmaceutical Sciences)
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2017 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 18, no 12, article id 2701Article in journal (Refereed) Published
Abstract [en]

The content of hyaluronan (HA) in the interstitium of the renal medulla changes in relation to body hydration status. We investigated if hormones of central importance for body fluid homeostasis affect HA production by renomedullary interstitial cells in culture (RMICs). Simultaneous treatment with vasopressin and angiotensin II (Ang II) reduced HA by 69%. No change occurred in the mRNA expressions of hyaluronan synthase 2 (HAS2) or hyaluronidases (Hyals), while Hyal activity in the supernatant increased by 67% and CD44 expression reduced by 42%. The autocoid endothelin (ET-1) at low concentrations (10-10 and 10-8 M) increased HA 3-fold. On the contrary, at a high concentration (10-6 M) ET-1 reduced HA by 47%. The ET-A receptor antagonist BQ123 not only reversed the reducing effect of high ET-1 on HA, but elevated it to the same level as low concentration ET-1, suggesting separate regulating roles for ET-A and ET-B receptors. This was corroborated by the addition of ET-B receptor antagonist BQ788 to low concentration ET-1, which abolished the HA increase. HAS2 and Hyal2 mRNA did not alter, while Hyal1 mRNA was increased at all ET-1 concentrations tested. Hyal activity was elevated the most by high ET-1 concentration, and blockade of ET-A receptors by BQ123 prevented about 30% of this response. The present study demonstrates an important regulatory influence of hormones involved in body fluid balance on HA handling by RMICs, thereby supporting the concept of a dynamic involvement of interstitial HA in renal fluid handling.

Place, publisher, year, edition, pages
2017. Vol. 18, no 12, article id 2701
Keywords [en]
angiotensin II, endothelin, hyaluronan, interstitium, kidney, medulla, vasopressin
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:rkh:diva-1087DOI: 10.3390/ijms18122701PubMedID: 29236055OAI: oai:DiVA.org:rkh-1087DiVA, id: diva2:750760
Funder
Swedish Research Council
Note

As manuscript in dissertation with title Hyaluronan turnover by renomedullary interstitial cells. Influence of fluid regulating hormones

Available from: 2013-10-25 Created: 2014-09-26 Last updated: 2018-08-30Bibliographically approved
In thesis
1. Regulation of Renal Hyaluronan in Water Handling: Studies in vivo and in vitro
Open this publication in new window or tab >>Regulation of Renal Hyaluronan in Water Handling: Studies in vivo and in vitro
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hyaluronan (HA) is a negatively charged extracellular matrix (ECM) component with water-attracting properties. It is the dominating ECM component in the renal medullary interstitium, where the amount changes in relation to hydration status: it increases during hydration and decreases during dehydration. It has, therefore, been suggested that HA participates in the regulation of renal fluid handling by changing the permeability properties of the interstitial space. This thesis investigates potential mechanisms for such a role in renal fluid regulation.

The results demonstrate that the high renal HA content of late nephrogenesis decreases during the completion of kidney development in the rat, which takes place in the neonatal period. The heterogenous distribution of HA is mainly established during the first three weeks after birth. On day 21, the HA content is similar to that in the adult rat. The process is dependent on normal Ang II function. It primarily involves a reduction of HA synthase 2 expression and an increase of medullary hyaluronidase 1. 

The cortical accumulation of HA that results from neonatal ACE inhibition can partly explain the pathological condition of the adult kidney, which causes reduced urinary concentration ability and tubulointerstitial inflammation.

It is possible to reduce renomedullary HA with the HA synthesis inhibitor 4-MU, and the kidney’s ability to respond to a hydration challenge will then be suppressed, without affecting GFR. 

The investigation of renomedullary interstitial cells (RMIC) in culture, shows that media osmolality and hormones of central importance for body fluid homeostasis, such as angiotensin II, ADH and endothelin, affect HA turnover through their effect on the RMICs, in a manner comparable to that found in vivo during changes in hydration status. 

In established streptozotocin-induced diabetes, HA is regionally accumulated in the kidney, proteinuria and polyuria, reduced urine osmolality, and reduced response to ADH V2 activation will occur. As opposed to the proteinuria, the HA accumulation is not sensitive to mTOR inhibition, suggesting an alternate pathway compared to other ECM components 

Taken together, the data suggest that during normal physiological conditions, renomedullary interstitial HA participates in renal fluid handling by affecting the interstitial prerequisites for fluid flux across the interstitial space. This is possible due to the water-attracting and physicochemical properties of this glycosaminoglycan. During pathological conditions, such as diabetes, the elevated interstitial HA can contribute to the defective kidney function, due to the proinflammatory and water-attracting properties of HA.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. p. 76
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 951
Keywords
Kidney, water balance, fluid handling, diabetes, nephropathy, ACE fetopathy, reabsorption, hyaluronic acid, glycosaminoglycan, GAG, extracellular matrix, mTOR, rapamycin, streptozotocin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:rkh:diva-1083 (URN)978-91-554-8800-0 (ISBN)
Public defence
2013-12-14, A1:107a, Biomedical center, Husargatan 3, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2014-09-30 Created: 2014-09-26 Last updated: 2018-01-11Bibliographically approved

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