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  • 1.
    Hansell, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Stridh, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Renomedullary interstitial hyaluronan is important for hydration-induced diuresis2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26Article in journal (Other academic)
  • 2.
    Stridh, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Linköping university.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    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.

  • 3.
    Stridh, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    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.

  • 4.
    Stridh, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Red Cross Univ Coll, Dept Hlth Sci, Stockholm, Sweden..
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Takahashi, Tomoko
    Hoshi Univ, Fac Pharmaceut Sci, Tokyo 1428501, Japan..
    Ikegami-Kawai, Mayumi
    Hoshi Univ, Fac Pharmaceut Sci, Tokyo 1428501, Japan..
    Friederich, Malou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    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.

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