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  • 1.
    Bartlett, Christina S.
    et al.
    Northwestern Univ, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA.;Northwestern Univ, Div Nephrol & Hypertens, Chicago, IL 60611 USA..
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Quaggin, Susan E.
    Northwestern Univ, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA.;Northwestern Univ, Div Nephrol & Hypertens, Chicago, IL 60611 USA..
    Vascular Growth Factors and Glomerular Disease2016In: ANNUAL REVIEW OF PHYSIOLOGY, VOL 78, ANNUAL REVIEWS, 2016, p. 437-461Chapter in book (Refereed)
    Abstract [en]

    The glomerulus is a highly specialized microvascular bed that filters blood to form primary urinary filtrate. It contains four cell types: fenestrated endothelial cells, specialized vascular support cells termed podocytes, perivascular mesangial cells, and parietal epithelial cells. Glomerular cell-cell communication is critical for the development and maintenance of the glomerular filtration barrier. VEGF, ANGPT, EGF, SEMA3A, TGF-beta, and CXCL12 signal in paracrine fashions between the podocytes, endothelium, and mesangium associated with the glomerular capillary bed to maintain filtration barrier function. In this review, we summarize the current understanding of these signaling pathways in the development and maintenance of the glomerulus and the progression of disease.

  • 2.
    Bisson, Nicolas
    et al.
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Ruston, Julie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Vanderlaan, Rachel
    Hardy, W Rod
    Du, Jianmei
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Hussein, Samer M
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Coward, Richard J
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Quaggin, Susan E
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Pawson, Tony
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    The Adaptor Protein Grb2 Is Not Essential for the Establishment of the Glomerular Filtration Barrier2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11, p. e50996-Article in journal (Refereed)
    Abstract [en]

    The kidney filtration barrier is formed by the combination of endothelial cells, basement membrane and epithelial cells called podocytes. These specialized actin-rich cells form long and dynamic protrusions, the foot processes, which surround glomerular capillaries and are connected by specialized intercellular junctions, the slit diaphragms. Failure to maintain the filtration barrier leads to massive proteinuria and nephrosis. A number of proteins reside in the slit diaphragm, notably the transmembrane proteins Nephrin and Neph1, which are both able to act as tyrosine phosphorylated scaffolds that recruit cytoplasmic effectors to initiate downstream signaling. While association between tyrosine-phosphorylated Neph1 and the SH2/SH3 adaptor Grb2 was shown in vitro to be sufficient to induce actin polymerization, in vivo evidence supporting this finding is still lacking. To test this hypothesis, we generated two independent mouse lines bearing a podocyte-specific constitutive inactivation of the Grb2 locus. Surprisingly, we show that mice lacking Grb2 in podocytes display normal renal ultra-structure and function, thus demonstrating that Grb2 is not required for the establishment of the glomerular filtration barrier in vivo. Moreover, our data indicate that Grb2 is not required to restore podocyte function following kidney injury. Therefore, although in vitro experiments suggested that Grb2 is important for the regulation of actin dynamics, our data clearly shows that its function is not essential in podocytes in vivo, thus suggesting that Grb2 rather plays a secondary role in this process.

  • 3. Cai, Qing
    et al.
    Brissova, Marcela
    Reinert, Rachel B
    Pan, Fong Cheng
    Brahmachary, Priyanka
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Shostak, Alena
    Radhika, Aramandla
    Poffenberger, Greg
    Quaggin, Susan E
    Jerome, W Gray
    Dumont, Daniel J
    Powers, Alvin C
    Enhanced expression of VEGF-A in β cells increases endothelial cell number but impairs islet morphogenesis and β cell proliferation.2012In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 367, no 1, p. 40-54Article in journal (Refereed)
    Abstract [en]

    There is a reciprocal interaction between pancreatic islet cells and vascular endothelial cells (EC) in which EC-derived signals promote islet cell differentiation and islet development while islet cell-derived angiogenic factors promote EC recruitment and extensive islet vascularization. To examine the role of angiogenic factors in the coordinated development of islets and their associated vessels, we used a "tet-on" inducible system (mice expressing rat insulin promoter-reverse tetracycline activator transgene and a tet-operon-angiogenic factor transgene) to increase the β cell production of vascular endothelial growth factor-A (VEGF-A), angiopoietin-1 (Ang1), or angiopoietin-2 (Ang2) during islet cell differentiation and islet development. In VEGF-A overexpressing embryos, ECs began to accumulate around epithelial tubes residing in the central region of the developing pancreas (associated with endocrine cells) as early as embryonic day 12.5 (E12.5) and increased dramatically by E16.5. While α and β cells formed islet cell clusters in control embryos at E16.5, the increased EC population perturbed endocrine cell differentiation and islet cell clustering in VEGF-A overexpressing embryos. With continued overexpression of VEGF-A, α and β cells became scattered, remained adjacent to ductal structures, and never coalesced into islets, resulting in a reduction in β cell proliferation and β cell mass at postnatal day 1. A similar impact on islet morphology was observed when VEGF-A was overexpressed in β cells during the postnatal period. In contrast, increased expression of Ang1 or Ang2 in β cells in developing or adult islets did not alter islet differentiation, development, or morphology, but altered islet EC ultrastructure. These data indicate that (1) increased EC number does not promote, but actually impairs β cell proliferation and islet formation; (2) the level of VEGF-A production by islet endocrine cells is critical for islet vascularization during development and postnatally; (3) angiopoietin-Tie2 signaling in endothelial cells does not have a crucial role in the development or maintenance of islet vascularization.

  • 4. Crowley, Steven D
    et al.
    Vasievich, Matthew P
    Ruiz, Phillip
    Gould, Samantha K
    Parsons, Kelly K
    Pazmino, A Kathy
    Facemire, Carie
    Chen, Benny J
    Kim, Hyung-Suk
    Tran, Trinh T
    Pisetsky, David S
    Barisoni, Laura
    Prieto-Carrasquero, Minolfa C
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Foster, Mary H
    Coffman, Thomas M
    Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis2009In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 119, no 4, p. 943-53Article in journal (Refereed)
    Abstract [en]

    Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of glomerular diseases. To examine the role of type 1 angiotensin (AT1) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Faslpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT1A); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT1A deficiency was not protective against disease but instead substantially accelerated mortality, proteinuria, and kidney pathology. Increased disease severity was not a direct effect of immune cells, since transplantation of AT1A-deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT1B, and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT1A-deficient lpr mice, and they showed evidence of exaggerated AT1B receptor activation, including substantially increased podocyte injury and expression of inflammatory mediators. Administration of losartan, which blocks all type 1 angiotensin receptors, reduced markers of kidney disease, including proteinuria, glomerular pathology, and cytokine mRNA expression. Since AT1A-deficient lpr mice had low blood pressure, these findings suggest that activation of type 1 angiotensin receptors in the glomerulus is sufficient to accelerate renal injury and inflammation in the absence of hypertension.

  • 5. Ding, Mei
    et al.
    Coward, Richard J
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Kim, William
    Quaggin, Susan E
    Regulation of hypoxia-inducible factor 2-a is essential for integrity of the glomerular barrier2013In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, Vol. 304, no 1, p. F120-F126Article in journal (Refereed)
    Abstract [en]

    Deletion of the von Hippel-Lindau tumor suppressor (Vhl) gene from renal podocytes of mice (podVhl KO) leads to rapidly progressive glomerulonephritis (RPGN), a clinical syndrome characterized by rapid loss of renal function and crescents on renal biopsy. Genomic profiling of glomeruli isolated from podVhl knockout (KO) mice and from patients with RPGN identified a fingerprint of genes regulated by hypoxia-inducible factors (HIF), important substrates of the product of the VHL gene. Here, we show that stabilization of Hifs in podocytes is both required and sufficient for the glomerular phenotype observed in podVhl KO mice. Genetic deletion of the obligate dimerization partner Arnt/Hif1b that is essential for Hif transcriptional function rescues the phenotype. Conversely, stabilization of HIF2A alone in podocytes results in crescentic glomerular disease. Together, our results show that the Hif pathway and Hif2a in particular are key players in maintenance of the glomerular barrier.

  • 6. Gradin, Kathryn A
    et al.
    Zhu, Hong
    Jeansson, Marie
    Göteborgs Universitet.
    Simonsen, Ulf
    Enhanced neuropeptide Y immunoreactivity and vasoconstriction in mesenteric small arteries from the early non-obese diabetic mouse2006In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 539, no 3, p. 184-191Article in journal (Refereed)
    Abstract [en]

    The present study investigated whether sympathetic neurotransmission is altered at an early stage of diabetes in mesenteric small arteries isolated from female non-obese diabetic (NOD) and control animals without diabetes from the same mouse strain. The NOD diabetic mice had increased plasma glucose and hypertension. Confocal microscopy showed distribution of nerve terminals was similar, but immunoreaction intensity for neuropeptide Y (NPY) and tyrosine hydroxylase was higher in small arteries from NOD diabetic compared with NOD control mice. In the presence of prazosin and activated with vasopressin, electrical field stimulation evoked contractions which were more pronounced in mesenteric arteries from NOD diabetic versus NOD control mice and inhibited by the NPY Y(1) receptor antagonist, BIBP 3226. NPY concentration-response curves were leftward shifted in arteries from NOD diabetic versus NOD control both in arteries with and without endothelium, but not in the presence of the BIBP 3226. The present findings suggest that enhanced NPY content and vasoconstriction to NPY by activation of NPY Y(1) receptors in arteries from diabetic mice may contribute to the enhanced sympathetic nerve activity and vascular resistance in female non-obese early diabetic animals.

  • 7.
    Grudén, Stefan
    et al.
    LIDDS AB, Uppsala, Sweden.
    Sandelin, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Rasanen, Veera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. National Veterinary Institute (SVA), Department of Chemistry, Environment and Feed Hygiene, Uppsala, Sweden.
    Axén, Niklas
    LIDDS AB, Uppsala, Sweden.
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel2017In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 114, p. 186-193Article in journal (Refereed)
    Abstract [en]

    Background

    Docetaxel is a cytostatic agent approved for treatment of non-small cell lung cancer as well as other cancers. Although docetaxel is an effective cytostatic agent, its effectiveness in clinical practice is associated with a variety of acute and long term side-effects. To overcome systemic side-effects, a slow release formulation based on calcium sulfate with docetaxel for intra-tumoral administration was developed.

    Methods

    Two formulations with the calcium sulfate NanoZolid technology were generated with a twofold difference in docetaxel drug load. The formulations were injected intra-tumorally as a paste which solidified within the tumor. The effects of the two intra-tumoral injection formulations were tested in female mice (n = 60) inoculated with subcutaneous Lewis lung carcinoma cells. The two formulations were compared to systemic intraperitoneal injection of docetaxel and a placebo formulation without docetaxel. Tumor volumes were measured and systemic side-effects were evaluated using body weight and cell counts from whole blood as well as plasma concentrations.

    Results

    Both docetaxel formulations showed a significantly higher antitumor efficacy compared to placebo, which was comparable to that of systemic administration of docetaxel. Moreover, the intra-tumoral formulations with docetaxel showed reduced systemic toxicity compared to systemic treatment, including less weight loss and no decrease in blood cell counts.

    Conclusions

    The results suggest that intra-tumoral slow release calcium sulfate based formulations with docetaxel can be an alternative strategy as an efficient local antitumoral treatment with reduced systemic toxicity.

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  • 8. Hale, L J
    et al.
    Welsh, G I
    Perks, C M
    Hurcombe, J A
    Moore, S
    Hers, I
    Saleem, M A
    Mathieson, P W
    Murphy, A J
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Holly, J M
    Hardouin, S N
    Coward, R J
    Insulin-like growth factor-II is produced by, signals to and is an important survival factor for the mature podocyte in man and mouse2013In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 230, no 1, p. 95-106Article in journal (Refereed)
    Abstract [en]

    Podocytes are crucial for preventing the passage of albumin into the urine and, when lost, are associated with the development of albuminuria, renal failure and cardiovascular disease. Podocytes have limited capacity to regenerate, therefore pro-survival mechanisms are critically important. Insulin-like growth factor-II (IGF-II) is a potent survival and growth factor; however, its major function is thought to be in prenatal development, when circulating levels are high. IGF-II has only previously been reported to continue to be expressed in discrete regions of the brain into adulthood in rodents, with systemic levels being undetectable. Using conditionally immortalized human and ex vivo adult mouse cells of the glomerulus, we demonstrated the podocyte to be the major glomerular source and target of IGF-II; it signals to this cell via the IGF-I receptor via the PI3 kinase and MAPK pathways. Functionally, a reduction in IGF signalling causes podocyte cell death in vitro and glomerular disease in vivo in an aged IGF-II transgenic mouse that produces approximately 60% of IGF-II due to a lack of the P2 promoter of this gene. Collectively, this work reveals the fundamental importance of IGF-II in the mature podocyte for glomerular health across mammalian species.

  • 9. Haraldsson, Börje
    et al.
    Jeansson, Marie
    Göteborgs Universitet.
    Glomerular filtration barrier2009In: Current opinion in nephrology and hypertension, ISSN 1062-4821, E-ISSN 1473-6543, Vol. 18, no 4, p. 331-335Article in journal (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW: In 2008, more than 376 papers were published on the glomerular barrier. Most of them dealt with the podocyte and its role in kidney disease.

    RECENT FINDINGS: There is new information on signaling pathways that are utilized in podocytes during proteinuria. Interestingly, the glomerular endothelium, with its fenestrae and glycocalyx, seems to be important for the maintenance of an intact glomerular barrier. All new advances at the molecular level are compatible with a highly size and charge-selective glomerular membrane and refute the concept of a 'leaky' glomerular barrier with tubular retrieval of intact albumin. Still, the hypothesis has its advocates, keeping a stimulating 'charge debate' alive.

    SUMMARY: Glomerular diseases account for 90% of chronic kidney disease requiring dialysis and transplantation at an annual cost of $20 billion in the USA. In clinical practice, we lack specific treatment of these diseases, giving us plenty of room for improvement. Future research should be directed toward deeper understanding of the signaling pathways involved in different conditions of proteinuria, the cross-talk between cell types in the glomerulus, and the identification of novel targets for treatment of acquired kidney disease.

  • 10.
    Iacovos, Michael
    et al.
    Swiss Fed Inst Technol Lausanne EPFL, Swiss Inst Expt Canc Res, Sch Life Sci, Lausanne, Switzerland.
    Orebrand, Martina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lima, Marta
    Univ Toronto, Matrix Dynam Grp, Fac Dent, Toronto, ON, Canada.
    Pereira, Beatriz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Volpert, Olga
    Northwestern Univ, Dept Urol, RH Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA.
    Quaggin, Susan
    Northwestern Univ, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA.; Northwestern Univ, Div Nephrol & Hypertens, Chicago, IL 60611 USA. .
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Angiopoietin-1 deficiency increases tumor metastasis in mice2017In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, article id 539Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Angipoietin-1 activation of the tyrosine kinase receptor Tek expressed mainly on endothelial cells leads to survival and stabilization of endothelial cells. Studies have shown that Angiopoietin-1 counteracts permeability induced by a number of stimuli. Here, we test the hypothesis that loss of Angiopoietin-1/Tek signaling in the vasculature would increase metastasis.

    METHODS:

    Angiopoietin-1 was deleted in mice just before birth using floxed Angiopoietin-1 and Tek mice crossed to doxycycline-inducible bitransgenic ROSA-rtTA/tetO-Cre mice. By crossing Angiopoietin-1 knockout mice to the MMTV-PyMT autochthonous mouse breast cancer model, we investigated primary tumor growth and metastasis to the lung. Furthermore, we utilized B16F10 melanoma cells subcutaneous and experimental lung metastasis models in Angiopoietin-1 and Tek knockout mice.

    RESULTS:

    We found that primary tumor growth in MMTV-PyMT mice was unaffected, while metastasis to the lung was significantly increased in Angiopoietin-1 knockout MMTV-PyMT mice. In addition, angiopoietin-1 deficient mice exhibited a significant increase in lung metastasis of B16F10 melanoma cells, compared to wild type mice 3 weeks after injection. Additional experiments showed that this was likely an early event due to increased attachment or extravasation of tumor cells, since seeding of tumor cells was significantly increased 4 and 24 h post tail vein injection. Finally, using inducible Tek knockout mice, we showed a significant increase in tumor cell seeding to the lung, suggesting that Angiopoietin-1/Tek signaling is important for vascular integrity to limit metastasis.

    CONCLUSIONS:

    This study show that loss of the Angiopoietin-1/Tek vascular growth factor system leads to increased metastasis without affecting primary tumor growth.

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  • 11.
    Jeansson, Marie
    et al.
    Göteborgs Universitet.
    Björck, Karin
    Tenstad, Olav
    Haraldsson, Börje
    Adriamycin alters glomerular endothelium to induce proteinuria2009In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, : JASN, Vol. 20, no 1, p. 114-122Article in journal (Refereed)
    Abstract [en]

    The pathophysiology underlying the nephrotic syndrome is becoming clear for several inherited podocytopathies; the mechanisms of injury that lead to the acquired forms of this disease are not well understood. We explored these mechanisms using the mouse model of adriamycin-induced proteinuria.We estimated the fractional clearances for FITC-Ficolls, albumin, and neutral albumin in cooled, isolated,perfused kidneys (cIPK) in situ. Treatment with adriamycin led to a significant increase in the fractional clearance of albumin and of Ficoll with radii larger than 20 A. Neutral albumin (33.4 A) and similarly sized Ficoll behaved similarly to each other. In addition, adriamycin led to a significant loss of charge density and size selectivity of the glomerular barrier. The thickness of the glomerular endothelial surface layer(i.e., or the glycocalyx) in adriamycin-treated animals was only 20% of that in normal animals. Finally,several proteoglycans were downregulated in isolated glomeruli. In summary, adriamycin thins the glomerular glycocalyx, perhaps by downregulating proteoglycan synthesis, and alters glomerular charge- and size selectivity. These data suggest that the glomerular endothelium may play a role in the pathogenesis of proteinuric renal diseases.

  • 12.
    Jeansson, Marie
    et al.
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hopsital.
    Gawlik, Alexander
    Anderson, Gregory
    Li, Chengjin
    Kerjaschki, Dontscho
    Henkelman, Mark
    Quaggin, Susan E
    Angiopoietin-1 is essential in mouse vasculature during development and in response to injury2011In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 121, no 6, p. 2278-2289Article in journal (Refereed)
    Abstract [en]

    Angiopoietin-1/Tek signaling is a critical regulator of blood vessel development, with conventional knockout of angiopoietin-1 or Tek in mice being embryonically lethal due to vascular defects. In addition, angiopoietin-1 is thought to be required for the stability of mature vessels. Using a Cre-Lox conditional gene targeting approach, we have studied the role of angiopoietin-1 in embryonic and adult vasculature. We report here that angiopoietin-1 is critical for regulating both the number and diameter of developing vessels but is not required for pericyte recruitment. Cardiac-specific knockout of angiopoietin-1 reproduced the phenotype of the conventional knockout, demonstrating that the early vascular abnormalities arise from flow-dependent defects. Strikingly, deletion in the entire embryo after day E13.5 produced no immediate vascular phenotype. However, when combined with injury or microvascular stress, angiopoietin-1 deficiency resulted in profound organ damage, accelerated angiogenesis, and fibrosis. These findings redefine our understanding of the biological roles of angiopoietin-1: it is dispensable in quiescent vessels but has a powerful ability to modulate the vascular response after injury.

  • 13.
    Jeansson, Marie
    et al.
    Göteborgs Universitet.
    Granqvist, A Björnson
    Nyström, J Sörensson
    Haraldsson, Börje
    Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice2006In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 49, no 9, p. 2200-2209Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: Despite the fact that diabetic nephropathy is an increasingly common disorder that may lead to uraemia, the underlying mechanisms are still poorly understood and there is no specific therapy. To clarify whether long-term diabetes alters glomerular size- or charge-selectivity or both, we studied non-obese diabetic mice for up to 40 weeks.

    MATERIALS AND METHODS: During the study period, spot urine was collected and blood pressure measured. At weeks 10 and 40, the right kidney was isolated and perfused at 8 degrees C to inhibit tubular function, allowing for analysis of glomerular selectivity with albumin and Ficoll clearance. The left kidney was removed for further investigation using electron microscopy and molecular biology. Real-time PCR with low-density arrays was done to evaluate renal cortex mRNA expression of proteoglycans and other components in the glomerular barrier. After 40 weeks of diabetes, kidneys showed morphological changes typical of diabetic complications.

    RESULTS: At 40 weeks, the fractional clearance for negatively charged albumin was three times higher in the diabetic animals (0.0160) than in controls (0.0051, p<0.001), while fractional clearance for neutral Ficoll 35.5 A with a Stokes Einstein radius similar to that of albumin was unaffected. In addition, protein and mRNA levels for versican and decorin were downregulated after 40 weeks of diabetes.

    CONCLUSIONS/INTERPRETATION: We conclude that glomerular charge- but not size-selectivity was impaired in the diabetic animals with proteinuria. Also, glomerular components such as versican, decorin and fibromodulin were found to be downregulated after 40 weeks of diabetes.

  • 14.
    Jeansson, Marie
    et al.
    Göteborgs Universitet.
    Haraldsson, Börje
    Glomerular size and charge selectivity in the mouse after exposure to glucosaminoglycan-degrading enzymes2003In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 14, no 7, p. 1756-1765Article in journal (Refereed)
    Abstract [en]

    This is the first functional study of glomerular size and charge selectivity in mice. The aim was to investigate the controversial issue of glomerular permselectivity in animals exposed to glucosaminoglycan-degrading enzymes, hyaluronidase, and heparinase. Fractional clearances (theta) for FITC-Ficoll and albumin were estimated in isoflurane anesthetized mice in vivo and in cooled isolated perfused kidneys (cIPK). In cIPK, a significant increase of theta(albumin) from 0.0023 (95% confidence interval, 0.0014 to 0.0033) in controls to 0.0130 (95% confidence interval, 0.0055 to 0.0206) was seen after hyaluronidase treatment. The theta for neutral Ficoll of similar size as albumin was 0.063 to 0.093 in all groups. According to a heterogeneous charged fiber model, the fiber volume fraction of negatively charged fibers decreased by 10% after enzyme treatments. It is concluded that glomerular size and charge selectivity in mice is similar to that previously shown for rats. Moreover, hyaluronic acid, chondroitin sulfate, and heparan sulfate are of importance for charge selectivity.

  • 15.
    Jeansson, Marie
    et al.
    Göteborgs Universitet.
    Haraldsson, Börje
    Morphological and functional evidence for an important role of the endothelial cell glycocalyx in the glomerular barrier2006In: American Journal of Physiology - Renal Physiology, ISSN 0363-6127, E-ISSN 1522-1466, American journal of physiology., Vol. 290, no 1, p. F111-F116Article in journal (Refereed)
    Abstract [en]

    In this study, we pursued the somewhat controversial issue whether the glycosaminoglycans (GAG) in the endothelial cell glycocalyx are important for glomerular size and charge selectivity. In isoflurane-anesthetized mice, Intralipid droplets were used as indirect markers of the glomerular endothelial cell-surface layer, i.e., the glycocalyx. The mice were given intravenous injections of GAG-degrading enzymes, which due to their high molecular weight remained and acted intravascularly. Flow-arrested kidneys were fixed and prepared for electron microscopy, and the distance between glomerular endothelial cells and the luminal Intralipid droplets was measured. The relative frequency of Intralipid droplets was calculated for each 50-nm increment zone up to 500 nm from the endothelial cell membrane surface as were the mean distances. Glomerular size and charge selectivity were estimated from the clearance data for neutral Ficolls (molecular radii of 12-72 A), and albumin in isolated kidneys was perfused at 8 degrees C. In enzyme-treated animals (hyaluronidase, heparinase, and chondroitinase), the relative Intralipid droplet frequency in the zone closest to the endothelial cells, i.e., 0-50 nm, was increased approximately 2.5 times compared with controls. Also, the mean distance between the Intralipid droplets and the endothelium was decreased from 176 to 115-122 nm by enzyme treatment. These changes were accompanied by an increase in the fractional clearance for albumin. In conclusion, both morphological and functional measurements suggest the endothelial cell glycocalyx to be an important component of the glomerular barrier.

  • 16. Jin, Jing
    et al.
    Sison, Karen
    Li, Chengjin
    Tian, Ruijun
    Wnuk, Monika
    Sung, Hoon-Ki
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Zhang, Cunjie
    Tucholska, Monika
    Jones, Nina
    Kerjaschki, Dontscho
    Shibuya, Masabumi
    Fantus, I George
    Nagy, Andras
    Gerber, Hans-Peter
    Ferrara, Napoleone
    Pawson, Tony
    Quaggin, Susan E
    Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function2012In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 151, no 2, p. 384-399Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor and its receptors, FLK1/KDR and FLT1, are key regulators of angiogenesis. Unlike FLK1/KDR, the role of FLT1 has remained elusive. FLT1 is produced as soluble (sFLT1) and full-length isoforms. Here, we show that pericytes from multiple tissues produce sFLT1. To define the biologic role of sFLT1, we chose the glomerular microvasculature as a model system. Deletion of Flt1 from specialized glomerular pericytes, known as podocytes, causes reorganization of their cytoskeleton with massive proteinuria and kidney failure, characteristic features of nephrotic syndrome in humans. The kinase-deficient allele of Flt1 rescues this phenotype, demonstrating dispensability of the full-length isoform. Using cell imaging, proteomics, and lipidomics, we show that sFLT1 binds to the glycosphingolipid GM3 in lipid rafts on the surface of podocytes, promoting adhesion and rapid actin reorganization. sFLT1 also regulates pericyte function in vessels outside of the kidney. Our findings demonstrate an autocrine function for sFLT1 to control pericyte behavior.

  • 17.
    Loganathan, Krishnapriya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Salem Said, Ebtisam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Winterrowd, Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Orebrand, Martina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    He, Liqun
    Department of Neurosur gery, Tianjin Medical University General Hospital, Tianjin Neurolo gical Institute, Key Laborat ory of Post-Neur oinjury Neuro-Rep air and Regener ation in Central Nervous System, Ministry of Educatio n and Tianjin City, Tianjin, China,.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. ntegrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge , Sweden.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. ntegrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge , Sweden.
    Quaggin, Susan E
    Feinberg Cardiovas cular Research Institute, Northwestern University , Chicago, United States of America.
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Angiopoietin-1 deficiency increases renal capillary rarefaction and tubulointerstitial fibrosis in mice2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 1, article id e0189433Article in journal (Refereed)
    Abstract [en]

    Presence of tubulointerstitial fibrosis is predictive of progressive decline in kidney function, independent of its underlying cause. Injury to the renal microvasculature is a major factor in the progression of fibrosis and identification of factors that regulate endothelium in fibrosis is desirable as they might be candidate targets for treatment of kidney diseases. The current study investigates how loss of Angipoietin-1 (Angpt1), a ligand for endothelial tyrosine-kinase receptor Tek (also called Tie2), affects tubulointerstitial fibrosis and renal microvasculature. Inducible Angpt1 knockout mice were subjected to unilateral ureteral obstruction (UUO) to induce fibrosis, and kidneys were collected at different time points up to 10 days after obstruction. Staining for aSMA showed that Angpt1 deficient kidneys had significantly more fibrosis compared to wildtype mice 3, 6, and 10 days after UUO. Further investigation 3 days after UUO showed a significant increase of Col1a1 and vimentin in Angpt1 deficient mice, as well as increased gene expression of Tgfb1, Col1a1, Fn1, and CD44. Kidney injury molecule 1 (Kim1/Havcr1) was significantly more increased in Angpt1 deficient mice 1 and 3 days after UUO, suggesting a more severe injury early in the fibrotic process in Angpt1 deficient mice. Staining for endomucin showed that capillary rarefaction was evident 3 days after UUO and Angpt1 deficient mice had significantly less capillaries 6 and 10 days after UUO compared to UUO kidneys in wildtype mice. RNA sequencing revealed downregulation of several markers for endothelial cells 3 days after UUO, and that Angpt1 deficient mice had a further downregulation of Emcn, Plvap, Pecam1, Erg, and Tek. Our results suggest that loss of Angpt1 is central in capillary rarefaction and fibrogenesis and propose that manipulations to maintain Angpt1 levels may slow down fibrosis progression.

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  • 18. Maezawa, Yoshiro
    et al.
    Onay, Tuncer
    Scott, Rizaldy P
    Keir, Lindsay S
    Dimke, Henrik
    Li, Chengjin
    Eremina, Vera
    Maezawa, Yuko
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Shan, Jingdong
    Binnie, Matthew
    Lewin, Moshe
    Ghosh, Asish
    Miner, Jeffrey H
    Vainio, Seppo J
    Quaggin, Susan E
    Loss of the Podocyte-Expressed Transcription Factor Tcf21/Pod1 Results in Podocyte Differentiation Defects and FSGS2014In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 11, p. 2459-2470Article in journal (Refereed)
    Abstract [en]

    Podocytes are terminally differentiated cells with an elaborate cytoskeleton and are critical components of the glomerular barrier. We identified a bHLH transcription factor, Tcf21, that is highly expressed in developing and mature podocytes. Because conventional Tcf21 knockout mice die in the perinatal period with major cardiopulmonary defects, we generated a conditional Tcf21 knockout mouse to explore the role of this transcription factor in podocytes in vivo. Tcf21 was deleted from podocytes and podocyte progenitors using podocin-cre (podTcf21) and wnt4-cre (wnt4creTcf21) driver strains, respectively. Loss of Tcf21 from capillary-loop stage podocytes (podTcf21) results in simplified glomeruli with a decreased number of endothelial and mesangial cells. By 5 weeks of age, 40% of podTcf21 mice develop massive proteinuria and lesions similar to FSGS. Notably, the remaining 60% of mice do not develop proteinuria even when aged to 8 months. By contrast, earlier deletion of Tcf21 from podocyte precursors (wnt4creTcf21) results in a profound developmental arrest of podocyte differentiation and renal failure in 100% of mice during the perinatal period. Taken together, our results demonstrate a critical role for Tcf21 in the differentiation and maintenance of podocytes. Identification of direct targets of this transcription factor may provide new therapeutic avenues for proteinuric renal disease, including FSGS.

  • 19.
    Sandelin, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Akad Sjukhuset, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Gruden, S.
    LIDDS AB, Uppsala, Sweden..
    Räsänen, Veera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Akad Sjukhuset, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Hedeland, M.
    Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, Uppsala, Sweden..
    Axen, N.
    LIDDS AB, Uppsala, Sweden..
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Akad Sjukhuset, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel2017In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no S2, article id 40PArticle in journal (Other academic)
  • 20. Singh, Sunita K S
    et al.
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Quaggin, Susan E
    New insights into the pathogenesis of cellular crescents2011In: Current opinion in nephrology and hypertension, ISSN 1062-4821, E-ISSN 1473-6543, Current opinion in, Vol. 20, no 3, p. 258-262Article in journal (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW: This review discusses the recent evidence that intrinsic glomerular cells including podocytes, parietal epithelial cells and progenitor cells within Bowman's capsule contribute to cellular crescents.

    RECENT FINDINGS: Using a variety of newer molecular markers and lineage tracing experiments, investigators have clearly demonstrated that glomerular cells play a key role in the development and progression of cellular crescents in experimental and human disease.

    SUMMARY: Crescentic glomerulonephritis is associated with significant morbidity and mortality. Current therapies target the immune system. The recent finding that nonimmune cells also play a role in crescent formation highlights the need to identify alternate and complimentary therapeutic strategies.

  • 21.
    Sivaskandarajah, Gavasker A
    et al.
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Maezawa, Yoshiro
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Eremina, Vera
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Baelde, Hans J
    Quaggin, Susan E
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Vegfa protects the glomerular microvasculature in diabetes2012In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 61, no 11, p. 2958-2966Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor A (VEGFA) expression is increased in glomeruli in the context of diabetes. Here, we tested the hypothesis that this upregulation of VEGFA protects the glomerular microvasculature in diabetes and that therefore inhibition of VEGFA will accelerate nephropathy. To determine the role of glomerular Vegfa in the development and progression of diabetic nephropathy, we used an inducible Cre-loxP gene-targeting system that enabled genetic deletion of Vegfa selectively from glomerular podocytes of wild-type or diabetic mice. Type 1 diabetes was induced in mice using streptozotocin (STZ). We then assessed the extent of glomerular dysfunction by measuring proteinuria, glomerular pathology, and glomerular cell apoptosis. Vegfa expression increased in podocytes in the STZ model of diabetes. After 7 weeks of diabetes, diabetic mice lacking Vegfa in podocytes exhibited significantly greater proteinuria with profound glomerular scarring and increased apoptosis compared with control mice with diabetes or Vegfa deletion without diabetes. Reduced local production of glomerular Vegfa in a mouse model of type 1 diabetes promotes endothelial injury accelerating the progression of glomerular injury. These results suggest that upregulation of VEGFA in diabetic kidneys protects the microvasculature from injury and that reduction of VEGFA in diabetes may be harmful.

  • 22. Thomson, Benjamin R
    et al.
    Heinen, Stefan
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Ghosh, Asish K
    Fatima, Anees
    Sung, Hoon-Ki
    Onay, Tuncer
    Chen, Hui
    Yamaguchi, Shinji
    Economides, Aris N
    Flenniken, Ann
    Gale, Nicholas W
    Hong, Young-Kwon
    Fawzi, Amani
    Liu, Xiaorong
    Kume, Tsutomu
    Quaggin, Susan E
    A lymphatic defect causes ocular hypertension and glaucoma in mice2014In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 10, p. 4320-4324Article in journal (Refereed)
    Abstract [en]

    Glaucoma is a leading cause of blindness, afflicting more than 60 million people worldwide. Increased intraocular pressure (IOP) due to impaired aqueous humor drainage is a major risk factor for the development of glaucoma. Here, we demonstrated that genetic disruption of the angiopoietin/TIE2 (ANGPT/TIE2) signaling pathway results in high IOP, buphthalmos, and classic features of glaucoma, including retinal ganglion degeneration and vision loss. Eyes from mice with induced deletion of Angpt1 and Angpt2 (A1A2FloxWB mice) lacked drainage pathways in the corneal limbus, including Schlemm’s canal and lymphatic capillaries, which share expression of the PROX1, VEGFR3, and FOXC family of transcription factors. VEGFR3 and FOXCs have been linked to lymphatic disorders in patients, and FOXC1 has been linked to glaucoma. In contrast to blood endothelium, in which ANGPT2 is an antagonist of ANGPT1, we have shown that both ligands cooperate to regulate TIE2 in the lymphatic network of the eye. While A1A2FloxWB mice developed high IOP and glaucoma, expression of ANGPT1 or ANGPT2 alone was sufficient for ocular drainage. Furthermore, we demonstrated that loss of FOXC2 from lymphatics results in TIE2 downregulation, suggesting a mechanism for ocular defects in patients with FOXC mutations. These data reveal a pathogenetic and molecular basis for glaucoma and demonstrate the importance of angiopoietin ligand cooperation in the lymphatic endothelium.

  • 23. Welsh, Gavin I
    et al.
    Hale, Lorna J
    Eremina, Vera
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Maezawa, Yoshiro
    Lennon, Rachel
    Pons, Deborah A
    Owen, Rachel J
    Satchell, Simon C
    Miles, Mervyn J
    Caunt, Christopher J
    McArdle, Craig A
    Pavenstädt, Hermann
    Tavaré, Jeremy M
    Herzenberg, Andrew M
    Kahn, C Ronald
    Mathieson, Peter W
    Quaggin, Susan E
    Saleem, Moin A
    Coward, Richard J M
    Insulin signaling to the glomerular podocyte is critical for normal kidney function2010In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 12, no 4, p. 329-340Article in journal (Refereed)
    Abstract [en]

    Diabetic nephropathy (DN) is the leading cause of renal failure in the world. It is characterized by albuminuria and abnormal glomerular function and is considered a hyperglycemic "microvascular" complication of diabetes, implying a primary defect in the endothelium. However, we have previously shown that human podocytes have robust responses to insulin. To determine whether insulin signaling in podocytes affects glomerular function in vivo, we generated mice with specific deletion of the insulin receptor from their podocytes. These animals develop significant albuminuria together with histological features that recapitulate DN, but in a normoglycemic environment. Examination of "normal" insulin-responsive podocytes in vivo and in vitro demonstrates that insulin signals through the MAPK and PI3K pathways via the insulin receptor and directly remodels the actin cytoskeleton of this cell. Collectively, this work reveals the critical importance of podocyte insulin sensitivity for kidney function.

1 - 23 of 23
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