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  • 1.
    Hansell, Peter
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Stridh, Sara
    Uppsala universitet, Integrativ Fysiologi.
    Renomedullary interstitial hyaluronan is important for hydration-induced diuresis2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, p. 1100.1-Article in journal (Other academic)
  • 2.
    Nordquist, Lina
    et al.
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Kallas, Åsa
    Stridh, Sara
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Palm, Fredrik
    Uppsala universitet, Institutionen för medicinsk cellbiologi.
    Wahren, John
    Renoprotective Effects of C-Peptide on Type 1 Diabetes2011In: Diabetes and C-peptide: Scientific and Clinical Aspects / [ed] Sima, Anders A.F., New York, NY: Humana Press, 2011, 1, p. 67-77Chapter in book (Refereed)
  • 3.
    Nordquist, Lina
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Stridh, Sara
    Uppsala universitet, Integrativ Fysiologi.
    Effects of proinsulin C-peptide on oxygen transport, uptake and utilization in insulinopenic diabetic subjects: a review2009In: Oxygen Transport to Tissue XXX / [ed] Liss, Per, Hansell, Peter, Bruley, Duane F., New York: Springer, 2009, Vol. 645, p. 193-198Conference paper (Refereed)
    Abstract [en]

    Exogenous C-peptide administration has beneficial effects in many of the tissues commonly affected by diabetic complications. Diabetes-induced circulatory impairments such as decreased blood flow are prevented by C-peptide, possibly via Ca2+-mediated effects on nitric oxide release. C-peptide also improves diabetes-induced erythrocyte deformability, which likely improves oxygen availability and uptake in affected tissues. Furthermore, C-peptide prevents diabetic neuropathy via improvements of endoneural blood flow and by preventing axonal swelling. In the kidney, C-peptide normalizes the diabetes-induced increase in oxygen consumption via inhibition of the Na+/K+-ATPase. Surprisingly, C-peptide has also been shown to prevent complications in patients with type II diabetes. Taken together, these results may indicate that C-peptide treatment has the potential to reduce the prevalence of diabetic complications. In this paper, the current knowledge regarding these beneficial effects of C-peptide administered to diabetic subjects will be reviewed briefly.

  • 4.
    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.

  • 5.
    Stridh, Sara
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Kerjaschki, D
    Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria.
    Chen, Y
    Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Rügheimer, Louise
    Uppsala universitet, Integrativ Fysiologi.
    Åstrand, A B M
    Department of Physiology, Institute of Physiology and Pharmacology, Gothenburg University, Gothenburg, Sweden.
    Johnsson, Cecilia
    Uppsala universitet, Transplantationskirurgi.
    Friberg, P
    Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Olerud, Johan
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    Takahashi, T
    Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
    Ikegami-Kawai, M
    Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
    Hansell, Peter
    Uppsala universitet, Integrativ Fysiologi.
    Angiotensin converting enzyme inhibition blocks interstitial hyaluronan dissipation in the neonatal rat kidney via hyaluronan synthase 2 and hyaluronidase 12011In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 30, no 1, p. 62-69Article in journal (Refereed)
    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.

  • 6.
    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.

  • 7.
    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.

  • 8.
    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.

  • 9.
    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.

  • 10.
    Stridh, Sara
    et al.
    Uppsala universitet, Integrativ Fysiologi.
    Sällström, Johan
    Uppsala universitet, Integrativ Fysiologi.
    Fridén, Markus
    Uppsala universitet, Institutionen för farmaceutisk biovetenskap.
    Hansell, Peter
    Uppsala universitet, Integrativ Fysiologi.
    Nordquist, Lina
    Uppsala universitet, Integrativ Fysiologi.
    Palm, Fredrik
    Uppsala universitet, Integrativ Fysiologi.
    C-peptide normalizes glomerular filtration rate in hyperfiltrating conscious diabetic rats2009In: Oxygen Transport to Tissue XXX / [ed] Per Liss, New York: Springer, 2009, p. 219-225Chapter in book (Refereed)
    Abstract [en]

    Tubular electrolyte transport accounts for a major part of the oxygen consumed by the normal kidney. We have previously reported a close association between diabetes and increased oxygen usage, partly due to increased tubular electrolyte transport secondary to glomerular hyperfiltration during the early onset of diabetes. Several studies have shown that acute administration of C-peptide to diabetic rats with glomerular hyperfiltration results in normalized glomerular filtration rate (GFR). In this study, we validated a novel method for precise and repetitive GFR measurements in conscious rats and used C-peptide injection in diabetic rats for evaluation. First, GFR was determined in normoglycemic control rats before and after C-peptide administration. Thereafter, all rats were made diabetic by an i.v. streptozotocin injection. Fourteen days later, GFR was again determined before and after C-peptide administration. GFR was estimated from plasma clearance curves using a single bolus injection of FITC-inulin, followed by serial blood sampling over 155 min. FITC-inulin clearance was calculated using non-compartmental pharmacokinetic data analysis. Baseline GFR in normoglycemic controls was 2.10 +/- 0.18 ml/min, and was unaffected by C-peptide (2.23 +/- 0.14 ml/min). Diabetic rats had elevated GFR (3.06 +/- .034 ml/min), which was normalized by C-peptide (2.35 +/- 0.30 ml/min). In conclusion, the used method for estimation of GFR in conscious animals result in values that are in good agreement with those obtained from traditional GFR measurements on anaesthetized rats. However, multiple measurements from the same conscious subject can be obtained using this method. Furthermore, as previously shown on anaesthetized rats, C-peptide also normalizes GFR in hyperfiltrating conscious diabetic rats.

  • 11.
    Östlund, Britt
    et al.
    The Swedish Red Cross University College, Department of Health Sciences. KTH.
    Björling, Gunilla
    The Swedish Red Cross University College, Department of Health Sciences.
    Mattsson, Janet
    The Swedish Red Cross University College, Department of Health Sciences.
    Stridh, Sara
    The Swedish Red Cross University College, Department of Health Sciences.
    Sahlström, Madeleine
    The Swedish Red Cross University College, Department of Health Sciences.
    Technology in Health Care: A new research and teaching subject in collaboration between nursing science and engineering2017Conference paper (Refereed)
    Abstract [en]

    Today, health care systems face a number of challenges related to technological developments. This work in progress is a new Swedish initiative for collaboration between nursing science and engineering focusing digitization, demographics and participation. The initiative aims at understanding how digitization affects patients and health care professionals and the role of engineers and how this collaboration proactively contributes to systems that support caring and nursing. The presentation expects input on the programs substance and boundaries and whether this initiative is fruitful to create sustainable health care systems.

  • 12.
    Östlund, Britt
    et al.
    KTH.
    Björling, Gunilla
    The Swedish Red Cross University College, Department of Health Sciences.
    Stridh, Sara
    The Swedish Red Cross University College, Department of Health Sciences.
    Sahlström, Madeleine
    The Swedish Red Cross University College, Department of Health Sciences.
    Mattsson, Janet
    The Swedish Red Cross University College, Department of Health Sciences.
    Digitizing Health Care in Collaboration Between Nursing and Engineering: Two cases of strategic learning and implementationof robots in the homes of elderly people2018In: International Journal On Advances in Life Sciences, ISSN 1942-2660, E-ISSN 1942-2660, Vol. 10, no 1 & 2, p. 11-22Article in journal (Refereed)
    Abstract [en]

    Digitization exceeds the limits of healthcare meetings, which gives renewed relevance to examine the collaboration between engineers and nurses. Caring for people is no longer just something going on in the hospital but at new arenas at home and in the middle of people's everyday lives. In caring situations nurse's responsibility is, unlike the physician, to make observations and to follow in detail the patient's caring needs, and where engineers provide technological devices to support and monitor the course of the disease. When digitizing the caring situation person-centered care gets a new meaning. For engineers the understanding of how technology is contextualized and domesticated becomes even more important to make applications and systems work outside laboratories. This paper presents two cases of interaction between engineers and nurses aimed at improving the implementation of robots and sensorsin elderly people ́s homes; and learning how to improve patient safety in hospitals.The result shows that conflicting epistemologies, differences in professional languages and lack of joint learning opportunities are factors that create obstacles for interactions. The conclusionsreject the idea of linear innovation processes and showthat successful ccollaborationtake more than just adding two and two together. Especially digitization is breaking up traditional barriers and hierarchies. For nurses to be proactive requires knowledge about technological developments and the ability toparticipate in design and innovation processes. For engineers a more thorough understanding of caring situations and users will contribute to a more reliable provision of digitalsolutions and point at new ideas leading up to innovations. The main output of the paper is that it is deepening the understanding of what factors leading to successfulcollaborations between nursing and engineering and what are the missing links.

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