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  • 1.
    Christensen, Rosita
    Red Cross University College of Nursing.
    Anatomi och fysiologi för sjuksköterskor och annan hälso- och sjukvårdspersonal2012 (ed. 1)Book (Other academic)
  • 2.
    Christensen, Rosita
    Karolinska institutet.
    Fysiologiska och fysikaliska aspekter vid nedkylning av hud hos överhettad människa2008Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    I spåren av de globala klimatförändringarna förväntas värmeböljor öka i både frekvens och intensitet, inte bara på sydliga breddgrader utan även på de norra vilket kommer att leda till en ökad incidens av sjukliga tillstånd relaterade till överhettning. Omedelbar och snabb nedkylning av överhettade personer är av största vikt för att minimera morbiditet och mortalitet. Inom svensk sjukvård finns inga riktlinjer för det initiala omhändertagandet av personer drabbade av överhettning. Syftet med studien var att erhålla fördjupad inblick i människans termoreglering med fokus på: hudens cirkulatoriska respons vid nedkylning, effekter av olika metoder för kylning och identifiera när det föreligger ökad risk för överhettning. Metoder som användes var litteraturstudie, värmebalansberäkning och enkät. Resultatet visade att människans termoreglering är av komplex natur som till största del styrs via reglering av hudens genomblödning men de fysiologiska mekanismerna är ännu inte helt klarlagda. Effektiva metoder för kylning är helkroppsimmersion i cirkulerande kallt vatten eller fuktning av huden med kallt vatten och fläktning. Vattentemperatur för optimal kyleffekt är ännu inte fastställt. Värmebalansberäkningarna illustrerade att bästa kyleffekt, via evaporation och konvektion uppnås med att så stor yta som möjligt fuktas med vatten (etanol vid hög luftfuktighet), fläkthastighet 3 m/s, vindriktning tvärs kroppens längdriktning och hudblodflöde 90 l/m2h. Riskgrupper för ansträngningsutlöst värmeslag är t.ex. idrottare, militärer och räddningsarbetare.  Det klassiska värmeslaget drabbar främst äldre och småbarn, kroniskt sjuka, fysiskt och psykiskt funktionshindrade. Riskfaktorer är bl.a. hög luftfuktighet, infektion, vissa läkemedel, social isolering, institutionsboende och avsaknad av luftkonditionering. Telefonintervjuer bekräftade att det initiala medicinska omhändertagandet variera stort på regionsjukhusens akutmottagningar. Sammanfattningsvis behövs en större sammanställning av forskningsresultat kring överhettning och effekter av olika kylmetoder för skapande av riktlinjer. Utifrån denna studie rekommenderas, beroende på personens allmäntillstånd nedsänkning i kar med cirkulerande kallt vatten alternativt placering i näthängmatta eller sidoläge med kontinuerlig sprayning av vatten över hela kroppen samtidigt som fläktar blåser tvärs kroppens längdriktning.

     

  • 3. Edfeldt, Katarina
    Small Intestinal Neuroendocrine Tumours: Genetic and Epigenetic Studies and Novel Serum Biomarkers2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Small intestinal neuroendocrine tumours (SI-NETs) are rare, hormone producing and proliferate slowly. Patients usually display metastases at time of diagnosis, the tumours are difficult to cure, and the disease course is unpredictable.

    The gene expression pattern was investigated in paper I, with emphasis on aggressive disease and tumour progression. Expression microarrays were performed on 42 tumours. Unsupervised hierarchal clustering revealed three clusters that were correlated to clinical features, and expression changes from primary tumour to metastasis. Eight novel genes, ACTG2, GREM2, REG3A, TUSC2, RUNX1, TGFBR2, TPH1 and CDH6 may be of importance for tumour progression.

    In paper II, expression of ACTG2 was detected in a fraction of SI-NETs, but not in normal enterochromaffin cells. Inhibition of histone methyltransferase and transfection of miR-145 induced expression and no effect was seen after DNA methylation or selective EZH2 inhibition in vitro. miR-145 expression was reduced in metastases compared to primary tumours. Overexpression of ACTG2 inhibited cell growth, and inducing ACTG2 may have therapeutic effects.

    TCEB3C (Elongin A3) is located on chromosome 18 and is imprinted in some tissues. In paper III a reduced protein expression was detected. The gene was epigenetically repressed by both DNA and histone methylation in a tumour tissue specific context. The expression was also induced in primary cell cultures after DNA demethylation and pyrosequencing revealed promoter region hypermethylation. Overexpression of TCEB3C inhibited cell growth by 50%, suggesting TCEB3C to be a tumour suppressor gene.

    In paper IV, 69 biomarkers were analysed in blood serum using multiplex proximity ligation assay. Nineteen markers displayed different levels between patients and controls. In an extended cohort, ELISA analysis showed elevated serum levels of Mindin, DcR3 and TFF3 in patients and protein expression in tumour cells. High levels of DcR3 and TFF3 were associated with poor survival, and DcR3 may be a marker for liver metastases. Mindin, DcR3, and TFF3 are potential novel diagnostic biomarkers for SI-NETs.

  • 4.
    Edfeldt, Katarina
    et al.
    Uppsala universitet, Endokrinkirurgi.
    Bäcklin, Christofer
    Uppsala universitet, Cancerfarmakologi och beräkningsmedicin.
    Tiensuu Janson, Eva
    Uppsala universitet, Onkologisk endokrinologi.
    Westin, Gunnar
    Uppsala universitet, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Endokrinkirurgi.
    Novel Serum Biomarkers in Small Intestinal Neuroendocrine TumorsManuscript (preprint) (Other academic)
  • 5.
    Edfeldt, Katarina
    et al.
    Uppsala universitet, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Endokrinkirurgi.
    Westin, Gunnar
    Uppsala universitet, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Endokrinkirurgi.
    A Plausible Role for Actin Gamma Smooth Muscle 2 (ACTG2) in Small Intestinal Neuroendocrine Tumorgenesis2016In: BMC Endocrine Disorders, ISSN 1472-6823, E-ISSN 1472-6823, Vol. 16, article id 19Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) originate from the enterochromaffin cells in the ileum and jejunum. The knowledge about genetic and epigenetic abnormalities is limited. Low mRNA expression levels of actin gamma smooth muscle 2 (ACTG2) have been demonstrated in metastases relative to primary SI-NETs. ACTG2 and microRNA-145 (miR-145) are aberrantly expressed in other cancers and ACTG2 can be induced by miR-145. The aim of this study was to investigate the role of ACTG2 in small intestinal neuroendocrine tumorigenesis.

    METHODS: Protein expression was analyzed in SI-NETs (n = 24) and in enterochromaffin cells by immunohistochemistry. The cell line CNDT2.5 was treated with the histone methyltransferase inhibitor 3-deazaneplanocin A (DZNep), the selective EZH2 inhibitor EPZ-6438, or 5-aza-2'-deoxycytidine, a DNA hypomethylating agent. Cells were transfected with ACTG2 expression plasmid or miR-145. Western blotting analysis, quantitative RT-PCR, colony formation- and viability assays were performed. miR-145 expression levels were measured in tumors.

    RESULTS: Eight primary tumors and two lymph node metastases displayed variable levels of positive staining. Fourteen SI-NETs and normal enterochromaffin cells stained negatively. Overexpression of ACTG2 significantly inhibited CNDT2.5 cell growth. Treatment with DZNep or transfection with miR-145 induced ACTG2 expression (>10-fold), but no effects were detected after treatment with EPZ-6438 or 5-aza-2'-deoxycytidine. DZNep also induced miR-145 expression. SI-NETs expressed relatively low levels of miR-145, with reduced expression in metastases compared to primary tumors.

    CONCLUSIONS: ACTG2 is expressed in a fraction of SI-NETs, can inhibit cell growth in vitro, and is positively regulated by miR-145. Theoretical therapeutic strategies based on these results are discussed.

  • 6. Hellström, Per M.
    et al.
    Rudholm, Tobias
    Gillberg, Linda
    Theodorsson, Elvar
    Webb, Dominic
    Sanger, Gareth J.
    Näslund, Erik
    Gastrin Receptor Antagonist YF476: Effects on Gastric Acid Secretion, Regulatory Peptides and Receptor Gene Expression in Rats2011In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 140, no 5, p. S730-S730Article in journal (Other academic)
  • 7.
    Rudholm Feldreich, Tobias
    Karolinska Institutet.
    Gastric acid secretion and gut peptides: mechanisms involved in inflammatory response2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The regulation of gastric acid secretion is complex and involves endocrine, paracrine, and neurocrine mechanisms. Among these, the interconnecting cross-talk between different gut peptides is an important part in the control of acid secretion. The aims of this thesis were (1) to develop a new method of measuring intragastric pH for prolonged periods of time, and (2) apply developed and in-use methods using different substances and their impact on gastric acid secretion in vivo experiments on rats. (3) To study the changes in acid output and the migrating motor complex (MMC) when subjected to different substances, and (4) to further study the alterations in expression of different gut peptides in tissue samples in vitro, and the impact of inflammation in the gut. The novel Bravo model developed gave reliable recordings compared to the chronic fistula model. The pH rose during treatment with esomeprazole and the acid output in the fistula model decreased accordingly. Gut peptides ghrelin and somatostatin increased in plasma when subjected to esomeprazole treatment, while gastrin remained unchanged. Ghrelin administered in bolus doses increased the intragastric pH in accordance with previous experiments. The gut peptides somatostatin, neurotensin, and vasoactive intestinal peptide increased during pentagastrin-stimulated infusion and challenge with hydrochloric acid and polyethylene glycol both in plasma and intestinal perfusate, though the most pronounced elevation was seen in perfusate and with somatostatin. Gastrazole gave the most extensive inhibitory effect on acid secretion compared to ranitidine and esomeprazole. The CCK2-receptor antagonist YF476 inhibited acid secretion long-term and increased concentrations of ghrelin and somatostatin in plasma, but gastrin remained low. Tissue mRNA content of the peptides and their receptors were unchanged except for the ghrelin receptor. When subdued to NSAID gastrin, CCK2-receptor and iNOS increased in mRNA expression while other peptides and receptors were unchanged. Administration of NPS evoked a response in the MMC pattern with irregular spiking and prolonged cycle length of the activity fronts, and the mRNA expression of iNOS, TNF, and IL-1ß increased in the tissue. In conclusion, The Bravo model can be used as a complement to the chronic fistula model for measurements of pH. The regulation of gastric acid secretion is not only limited to the stomach, but also present in the smaller intestine where release of somatostatin seems to be most important. Different mechanisms are involved in the blockage of acid secretion when subjected to YF476, but under NSAID treatment the expression of gastrin and its receptor CCK2 increase and COX- 2 is activated which demonstrates a novel pathway for the study of gastric ulcerations. NPS, a novel neuropeptide influences the gastric motility and could have a role in inflammatory responses seen in the changes in the migrating motor complex and inflammatory markers iNOS, TNF, and IL-1ß.

  • 8. Rudholm, Tobias
    et al.
    Campbell, Colin A.
    Mclean, Peter G.
    Hellström, Per M.
    Näslund, Erik
    A novel method for studying intra-gastric pH over prolonged periods of time in freely moving rats2007In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 132, no 4, p. A606-A606Article in journal (Other academic)
  • 9. Rudholm, Tobias
    et al.
    Campbell, Colin A.
    McLean, Peter G.
    Hellström, Per M.
    Näslund, Erik
    A novel technique for prolonged studies of gastric acid secretion in free roaming conscious rats2006In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 130, no 4, p. A386-A386Article in journal (Other academic)
  • 10.
    Rudholm, Tobias
    et al.
    Departments of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Gillberg, L
    Departments of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Theodorsson, E
    Clinical Chemistry, Linköping University.
    Sanger, G
    Neurology and GI CEDD, GlaxoSmithKline, Harlow, UK.
    Campbell, C A
    Neurology and GI CEDD, GlaxoSmithKline, Harlow, UK.
    Boyce, M
    Hammersmith Medicines Research, London, UK.
    Näslund, E
    Clinical Sciences, Karolinska Institutet, Danderyd Hospital.
    Hellström, P M
    Medical Sciences, Gastro unit, Uppsala University.
    CCK2-receptor antagonist YF476 prevents NSAID-induced gastric ulceration through acid inhibition mediated by regulatory peptidesManuscript (preprint) (Other academic)
  • 11.
    Rudholm, Tobias
    et al.
    Departments of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Gillberg, L
    Departments of Medicine, Gastroenterology and Hepatology unit, Karolinska Institutet, Karolinska University Hospital.
    Webb, D L
    Department of Medical Sciences, Uppsala University.
    Näslund, E
    Clinical Sciences, Karolinska Institutet, Danderyd Hospital.
    Hellström, P M
    Medical Sciences, Gastro unit, Uppsala University.
    Neuropeptide S in the gastrointestinal tract: effects on motility and inflammatory markers TNF, IL-1β, and iNOS in the ratManuscript (preprint) (Other academic)
  • 12.
    Stridh, Sara
    Uppsala universitet, Integrativ Fysiologi.
    Regulation of Renal Hyaluronan in Water Handling: Studies in vivo and in vitro2013Doctoral 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.

  • 13.
    Stridh, Sara
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Hansell, Peter
    Uppsala universitet, Integrativ Fysiologi.
    Inhibition of hyaluronan synthesis in rats reduces renal ability to excrete fluid and electrolytes during acute hydration2013In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 4, p. 217-221Article in journal (Refereed)
    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.

  • 14.
    Stridh, Sara
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Hansell, Peter
    Uppsala universitet, Integrativ Fysiologi.
    Renal interstitial hyaluronan: functional aspects during normal and pathological conditions2012In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 302, no 11, p. R1235-R1249Article, review/survey (Refereed)
    Abstract [en]

    The glycosaminoglycan (GAG) hyaluronan (HA) is recognized as an important structural component of the extracellular matrix, but it also interacts with cells during embryonic development, wound healing, inflammation, and cancer; i.e., important features in normal and pathological conditions. The specific physico-chemical properties of HA enable a unique hydration capacity, and in the last decade it was revealed that in the interstitium of the renal medulla, where the HA content is very high, it changes rapidly depending on the body hydration status while the HA content of the cortex remains unchanged at very low amounts. The kidney, which regulates fluid balance, uses HA dynamically for the regulation of whole body fluid homeostasis. Renomedullary HA elevation occurs in response to hydration and during dehydration the opposite occurs. The HA-induced alterations in the physicochemical characteristics of the interstitial space affects fluid flux; i.e., reabsorption. Antidiuretic hormone, nitric oxide, angiotensin II, and prostaglandins are classical hormones/compounds involved in renal fluid handling and are important regulators of HA turnover during variations in hydration status. One major producer of HA in the kidney is the renomedullary interstitial cell, which displays receptors and/or synthesis enzymes for the hormones mentioned above. During several kidney disease states, such as ischemia-reperfusion injury, tubulointerstitial inflammation, renal transplant rejection, diabetes, and kidney stone formation, HA is upregulated, which contributes to an abnormal phenotype. In these situations, cytokines and other growth factors are important stimulators. The immunosuppressant agent cyclosporine A is nephrotoxic and induces HA accumulation, which could be involved in graft rejection and edema formation. The use of hyaluronidase to reduce pathologically overexpressed levels of tissue HA is a potential therapeutic tool since diuretics are less efficient in removing water bound to HA in the interstitium. Although the majority of data describing the role of HA originate from animal and cell studies, the available data from humans demonstrate that an upregulation of HA also occurs in diabetic kidneys, in transplant-rejected kidneys, and during acute tubular necrosis. This review summarizes the current knowledge regarding interstitial HA in the role of regulating kidney function during normal and pathological conditions. It encompasses mechanistic insights into the back-ground of the heterogeneous intrarenal distribution of HA; i.e., late nephrogenesis, its regulation during variations in hydration status, and its involvement during several pathological conditions. Changes in hyaluronan synthases, hyaluronidases, and binding receptor expression are discussed in parallel.

  • 15.
    Stridh, Sara
    et al.
    The Swedish Red Cross University College, Department of Health Sciences. Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Palm, Fredrik
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Takahashi, Tomoko
    Hoshi University, Tokyo, Japan .
    Ikegami-Kawai, Mayumi
    Hoshi University, Tokyo, Japan .
    Friederich-Persson, Malou
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Hansell, Peter
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Hyaluronan Production by Renomedullary Interstitial Cells: Influence of Endothelin, Angiotensin II and Vasopressin2017In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 18, no 12, article id 2701Article in journal (Refereed)
    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.

  • 16.
    Stridh, Sara
    et al.
    Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University.
    Palm, Fredrik
    Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University; Department of Medical and Health Sciences, Linköping University.
    Takahashi, Tomoko
    Hoshi University, Tokyo.
    Ikegami-Kawai, Mayumi
    Hoshi University, Tokyo, Japan .
    Hansell, Peter
    Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University.
    Inhibition of mTOR activity in diabetes mellitus reduces proteinuria but not renal accumulation of hyaluronan2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 4, p. 233-240Article in journal (Refereed)
    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.

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