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Regulation of Renal Hyaluronan in Water Handling: Studies in vivo and in vitro
Uppsala universitet, Integrativ Fysiologi.ORCID-id: 0000-0003-4092-2854
2013 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2013. , s. 76
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 951
Emneord [en]
Kidney, water balance, fluid handling, diabetes, nephropathy, ACE fetopathy, reabsorption, hyaluronic acid, glycosaminoglycan, GAG, extracellular matrix, mTOR, rapamycin, streptozotocin
HSV kategori
Identifikatorer
URN: urn:nbn:se:rkh:diva-1083Libris ID: 14808491ISBN: 978-91-554-8800-0 (tryckt)OAI: oai:DiVA.org:rkh-1083DiVA, id: diva2:750763
Disputas
2013-12-14, A1:107a, Biomedical center, Husargatan 3, 09:15 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2014-09-30 Laget: 2014-09-26 Sist oppdatert: 2018-01-11bibliografisk kontrollert
Delarbeid
1. Angiotensin converting enzyme inhibition blocks interstitial hyaluronan dissipation in the neonatal rat kidney via hyaluronan synthase 2 and hyaluronidase 1
Åpne denne publikasjonen i ny fane eller vindu >>Angiotensin converting enzyme inhibition blocks interstitial hyaluronan dissipation in the neonatal rat kidney via hyaluronan synthase 2 and hyaluronidase 1
Vise andre…
2011 (engelsk)Inngår i: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 30, nr 1, s. 62-69Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

A functional renin-angiotensin system (RAS) is required for normal kidney development. Neonatal inhibition of the RAS in rats results in long-term pathological renal phenotype and causes hyaluronan (HA), which is involved in morphogenesis and inflammation, to accumulate. To elucidate the mechanisms, intrarenal HA content was followed during neonatal completion of nephrogenesis with or without angiotensin converting enzyme inhibition (ACEI) together with mRNA expression of hyaluronan synthases (HAS), hyaluronidases (Hyal), urinary hyaluronidase activity and cortical lymphatic vessels, which facilitate the drainage of HA from the tissue. In 6-8days old control rats cortical HA content was high and reduced by 93% on days 10-21, reaching adult low levels. Medullary HA content was high on days 6-8 and then reduced by 85% to 12-fold above cortical levels at day 21. In neonatally ACEI-treated rats the reduction in HA was abolished. Temporal expression of HAS2 corresponded with the reduction in HA content in the normal kidney. In ACEI-treated animals cortical HAS2 remained twice the expression of controls. Medullary Hyal1 increased in controls but decreased in ACEI-treated animals. Urine hyaluronidase activity decreased with time in control animals while in ACEI-treated animals it was initially 50% lower and did not change over time. Cells expressing the lymphatic endothelial mucoprotein podoplanin in ACEI-treated animals were increased 18-fold compared to controls suggesting compensation. In conclusion, the high renal HA content is rapidly reduced due to reduced HAS2 and increased Hyal1 mRNA expressions. Normal angiotensin II function is crucial for inducing these changes. Due to the extreme water-attracting and pro-inflammatory properties of HA, accumulation in the neonatally ACEI-treated kidneys may partly explain the pathological renal phenotype of the adult kidney, which include reduced urinary concentration ability and tubulointerstitial inflammation.

Emneord
Nephrogenesis, Lymphatic vessel, Podoplanin, HAS2, Hyal1
HSV kategori
Identifikatorer
urn:nbn:se:rkh:diva-1089 (URN)10.1016/j.matbio.2010.09.006 (DOI)20933085 (PubMedID)
Tilgjengelig fra: 2011-04-18 Laget: 2014-09-26 Sist oppdatert: 2017-12-05bibliografisk kontrollert
2. Inhibition of hyaluronan synthesis in rats reduces renal ability to excrete fluid and electrolytes during acute hydration
Åpne denne publikasjonen i ny fane eller vindu >>Inhibition of hyaluronan synthesis in rats reduces renal ability to excrete fluid and electrolytes during acute hydration
2013 (engelsk)Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, nr 4, s. 217-221Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background. Hyaluronan (HA) is the dominant glycosaminoglycan in the renomedullary interstitium. Renomedullary HA has been implicated in tubular fluid handling due to its water-attracting properties and the changes occurring in parallel to acute variations in the body hydration status.

Methods. HA production was inhibited by 4-methylumbelliferone (4-MU in drinking water for 5 days, 1.45 ± 0.07 g/day/kg body weight) in rats prior to hydration.

Results. Following hypotonic hydration for 135 min in control animals, diuresis and osmotic excretion increased while sodium excretion and glomerular filtration rate (GFR) remained unchanged. The medullary and cortical HA contents were 7.85 ± 1.29 ng/mg protein and 0.08 ± 0.01 ng/mg protein, respectively. Medullary HA content after 4-MU was 38% of that in controls (2.98 ± 0.95 ng/g protein, p < 0.05), while the low cortical levels were unaffected. Baseline urine flow was not different from that in controls. The diuretic response to hydration was, however, only 51% of that in controls (157 ± 36 versus 306 ± 54 µl/g kidney weight/135 min, p < 0.05) and the osmolar excretion only 47% of that in controls (174 ± 47 versus 374 ± 41 µOsm/g kidney weight/135 min, p < 0.05). Sodium excretion, GFR, and arterial blood pressure were similar to that in control rats and unaltered during hydration.

Conclusions. Reduction of renomedullary interstitial HA using 4-MU reduces the ability of the kidney to respond appropriately upon acute hydration. The results strengthen the concept of renomedullary HA as a modulator of tubular fluid handling by changing the physicochemical properties of the interstitial space.

HSV kategori
Identifikatorer
urn:nbn:se:rkh:diva-1084 (URN)10.3109/03009734.2013.834013 (DOI)24102146 (PubMedID)
Tilgjengelig fra: 2013-10-25 Laget: 2014-09-26 Sist oppdatert: 2018-01-11bibliografisk kontrollert
3. Hyaluronan Production by Renomedullary Interstitial Cells: Influence of Endothelin, Angiotensin II and Vasopressin
Åpne denne publikasjonen i ny fane eller vindu >>Hyaluronan Production by Renomedullary Interstitial Cells: Influence of Endothelin, Angiotensin II and Vasopressin
Vise andre…
2017 (engelsk)Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 18, nr 12, artikkel-id 2701Artikkel i tidsskrift (Fagfellevurdert) 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.

Emneord
angiotensin II, endothelin, hyaluronan, interstitium, kidney, medulla, vasopressin
HSV kategori
Identifikatorer
urn:nbn:se:rkh:diva-1087 (URN)10.3390/ijms18122701 (DOI)29236055 (PubMedID)
Forskningsfinansiär
Swedish Research Council
Merknad

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

Tilgjengelig fra: 2013-10-25 Laget: 2014-09-26 Sist oppdatert: 2018-08-30bibliografisk kontrollert
4. Inhibition of mTOR activity in diabetes mellitus reduces proteinuria but not renal accumulation of hyaluronan
Åpne denne publikasjonen i ny fane eller vindu >>Inhibition of mTOR activity in diabetes mellitus reduces proteinuria but not renal accumulation of hyaluronan
Vise andre…
2015 (engelsk)Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, nr 4, s. 233-240Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

OBJECTIVES: Accumulation of extracellular matrix (ECM) components is an early sign of diabetic nephropathy. Also the glycosaminoglycan hyaluronan (HA) is elevated in the renal interstitium during experimental diabetes. The mammalian target of rapamycin (mTOR) pathway participates in the signaling of hyperglycemia-induced ECM accumulation in the kidney, but this has not yet been investigated for HA. We hypothesized that interstitial HA accumulation during diabetes may involve mTOR activation.

METHODS: Diabetic rats (6 weeks post-streptozotocin (STZ)) were treated with rapamycin to inhibit mTOR or vehicle for 2 additional weeks. Kidney function (glomerular filtration rate, renal blood flow, urine output) and regional renal HA content were thereafter analyzed. The ability of the animals to respond to desmopressin was also tested.

RESULTS: Diabetic animals displayed hyperglycemia, proteinuria, hyperfiltration, renal hypertrophy, increased diuresis with reduced urine osmolality, and reduced weight gain. Cortical and outer medullary HA was elevated in diabetic rats. Urine hyaluronidase activity was almost doubled in diabetic rats compared with controls. The ability to respond to desmopressin was absent in diabetic rats. Renal blood flow and arterial blood pressure were unaffected by the diabetic state. In diabetic rats treated with rapamycin the proteinuria was reduced by 32%, while all other parameters were unaffected.

CONCLUSION: Regional renal accumulation of the ECM component HA is not sensitive to mTOR inhibition by rapamycin, while proteinuria is reduced in established STZ-induced diabetes. Whether the diabetes-induced renal accumulation of HA occurs through different pathways than other ECM components, or is irreversible after being established, remains to be shown.

Emneord
Diabetes mellitus; hyaluronan; hyaluronidase; mTOR; nephropathy; rapamycin
HSV kategori
Identifikatorer
urn:nbn:se:rkh:diva-1086 (URN)10.3109/03009734.2015.1062442 (DOI)26175092 (PubMedID)
Merknad

Som manuskript i avhandling. As manuscript in dissertation.

Tilgjengelig fra: 2013-10-25 Laget: 2014-09-26 Sist oppdatert: 2018-01-11bibliografisk kontrollert

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