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Inhibition of mTOR activity in established diabetes reduces proteinuria but not renal accumulation of hyaluronan
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Hoshi University, Tokyo, Japan . (Faculty of Pharmaceutical Sciences)
Hoshi University, Tokyo, Japan . (Faculty of Pharmaceutical Sciences)
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2015 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 4, 233-240 p.Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
2015. Vol. 120, no 4, 233-240 p.
Keyword [en]
Diabetes mellitus; hyaluronan; hyaluronidase; mTOR; nephropathy; rapamycin
National Category
Cell and Molecular Biology
URN: urn:nbn:se:uu:diva-209761DOI: 10.3109/03009734.2015.1062442ISI: 000365684900002PubMedID: 26175092OAI: oai:DiVA.org:uu-209761DiVA: diva2:659439
Swedish Research Council, 10840
Available from: 2013-10-25 Created: 2013-10-25 Last updated: 2016-01-25Bibliographically 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. 76 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 951
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
urn:nbn:se:uu:diva-209763 (URN)978-91-554-8800-0 (ISBN)
Public defence
2013-12-14, A1:107a, Biomedical center, Husargatan 3, Uppsala, 09:15 (Swedish)
Available from: 2013-11-18 Created: 2013-10-25 Last updated: 2015-07-29Bibliographically approved

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Palm, FredrikHansell, Peter
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