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- Dunér, Fredrik, et al.
(författare)
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Permeability, ultrastructural changes, and distribution of novel proteins in the glomerular barrier in early puromycin aminonucleoside nephrosis.
- 2010
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Ingår i: Nephron. Experimental nephrology. - : S. Karger AG. - 1660-2129. ; 116:2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: It is still unclear what happens in the glomerulus when proteinuria starts. Using puromycin aminonucleoside nephrosis (PAN) rats, we studied early ultrastructural and permeability changes in relation to the expression of the podocyte-associated molecules nephrin, α-actinin, dendrin, and plekhh2, the last two of which were only recently discovered in podocytes. METHODS: Using immune stainings, semiquantitative measurement was performed under the electron microscope. Permeability was assessed using isolated kidney perfusion with tracers. Possible effects of ACE inhibition were tested. RESULTS: By day 2, some patchy foot process effacement, but no proteinuria, appeared. The amount of nephrin was reduced in both diseased and normal areas. The other proteins showed few changes, which were limited to diseased areas. By day 4, foot process effacement was complete and proteinuria appeared in parallel with signs of size barrier damage. Nephrin decreased further, while dendrin and plekhh2 also decreased but α-actinin remained unchanged. ACE inhibition had no significant protective effect. CONCLUSIONS: PAN glomeruli already showed significant pathology by day 4, despite relatively mild proteinuria. This was preceded by altered nephrin expression, supporting its pivotal role in podocyte morphology. The novel proteins dendrin and plekhh2 were both reduced, suggesting roles in PAN, whereas α-actinin was unchanged.
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- Dunér, Fredrik
(författare)
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Ultrastructural studies of the blood-urine barrier in proteinuric states
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The kidneys filter enormous amounts of blood every day, removing excess fluid and waste products while retaining cells and large proteins in the circulation. The podocytes with their foot processes and slit diaphragms (SD) are important components of the renal filter and the barrier function. Proteinuria is a leading sign of kidney disease, irrespective of the cause, and can in itself be harmful, accelerating the disease towards renal failure and the need for dialysis or transplantation. In this project, we used semiquantitative immunoelectron microscopy (iEM) to describe the distribution of novel podocyte proteins in diseases with foot process effacement (FPE), the most common ultrastructural finding in proteinuria. Study I: Expression of nephrin in minimal change nephrotic syndrome (MCNS). Under the light microscope, nephrin immunofluorescence (IFL) turned from a linear pattern along the glomerular capillary loops, into a course granular one. iEM showed a decreased nephrin labeling in MCNS, even in ultrastructurally normal podocytes. This implies a role for nephrin and the SD in the pathogenesis of MCNS. Study II: Dendrin is a novel intracellular protein in the SD region. We analyzed its expression in MCNS compared to ZO-1, a protein known to be stable in proteinuria. In areas with FPE, dendrin was redistributed from the SD to the podocyte cytoplasm, but in contrast to nephrin, there was no overall decrease. Thus, when compared to nephrin, dendrin seems less involved in the pathogenesis of FPE. Study III: To enable studies on novel podocyte proteins before and around the onset of proteinuria, an experimental model was used; puromycin aminoneucleoside nephrosis in rat (PAN). Nephrin, dendrin, plekhh2 and alpha-actinin-4 were studied. Thorough ultrastuctural analyses at different time-points in PAN were performed. alpha-actinin-4, a cytoskeleton cross-linker, did not change. Nephrin started to decrease on day two after induction, i.e. before the appearance of proteinuria. Dendrin and plekhh2 decreased on day four when the animals had massive proteinuria. We concluded that a disturbed expression of nephrin in PAN rats, similar to our findings in MCNS, seems to be related to the appearance of proteinuria. Changes in plekhh2 and dendrin on the other hand, could be secondary to FPE and loss of SDs. Study IV: Pdlim2 is a cytoskeleton-associated protein, not previously shown in the kidney. Here, its association with the actin cross-linker alpha-actinin-4 in the podocytes is demonstrated by several techniques. Under the electron microscope, it is found centrally in the foot processes, in association with the actin cytoskeleton. In patients with MCNS and membranous nephropathy (MN), the expression was significantly reduced, while it was preserved in FSGS patients. This implies that pdlim2 may have a specific role in the pathogenesis of MN and MCNS. In conclusion, we have developed a semiquantitative immuno-EM technique to study the expression of novel glomerular proteins in proteinuric rats, in normal human kidney, and in renal biopsies from patients with acquired renal diseases. Our studies have brought new information about the subcellular localization of these proteins. Furthermore, the expression patterns differ between diseases, indicating different roles in the pathogenesis of proteinuria.
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- Perisic, Ljubica, et al.
(författare)
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Plekhh2, a novel podocyte protein downregulated in human focal segmental glomerulosclerosis, is involved in matrix adhesion and actin dynamics
- 2012
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538 .- 1523-1755. ; 82:10, s. 1071-1083
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Tidskriftsartikel (refereegranskat)abstract
- Pleckstrin homology domain-containing, family H (with MyTH4 domain), member 2 (Plekhh2) is a 1491-residue intracellular protein highly enriched in renal glomerular podocytes for which no function has been ascribed. Analysis of renal biopsies from patients with focal segmental glomerulosclerosis revealed a significant reduction in total podocyte Plekhh2 expression compared to controls. Sequence analysis indicated a putative a-helical coiled-coil segment as the only recognizable domain within the N-terminal half of the polypeptide, while the C-terminal half contains two PH, a MyTH4, and a FERM domain. We identified a phosphatidylinositol-3-phosphate consensus-binding site in the PH1 domain required for Plekhh2 localization to peripheral regions of cell lamellipodia. The N-terminal half of Plekkh2 is not necessary for lamellipodial targeting but mediates self-association. Yeast two-hybrid screening showed that Plekhh2 directly interacts through its FERM domain with the focal adhesion protein Hic-5 and actin. Plekhh2 and Hic-5 coprecipitated and colocalized at the soles of podocyte foot processes in situ and Hic-5 partially relocated from focal adhesions to lamellipodia in Plekhh2-expressing podocytes. In addition, Plekhh2 stabilizes the cortical actin cytoskeleton by attenuating actin depolymerization. Our findings suggest a structural and functional role for Plekhh2 in the podocyte foot processes.
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- Sistani, Laleh, et al.
(författare)
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Pdlim2 is a novel actin-regulating protein of podocyte foot processes
- 2011
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538 .- 1523-1755. ; 80:10, s. 1045-1054
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Tidskriftsartikel (refereegranskat)abstract
- The slit diaphragm and the apical and basal membrane domains of podocytes are connected to each other by an actin-based cytoskeleton critical to the maintenance of the glomerular filtration barrier. In an effort to discover novel regulatory proteins of the podocyte foot process, we identified and characterized pdlim2, a member of the actin-associated LIM protein subfamily of cytosolic proteins typified by an N-terminal PDZ domain and a C-terminal LIM domain. In the kidney, the pdlim2 protein is highly specific for the glomerulus and podocyte foot processes as shown by RT-PCR, western blotting, immunofluorescence, and immunoelectron microscopy. In cultured podocytes, pdlim2 was associated with stress fibers and cortical actin. Pdlim2 seems to regulate actin dynamics in podocytes since stress fibers were stabilized in its presence. Mechanistically, pdlim2 interacts with two actin-associated podocyte proteins, alpha-actinin-4 and angiomotin-like-1, as shown by immunoprecipitation and yeast two-hybrid analyses. By semi-quantitative immunoelectron microscopy, there was a reduced expression of pdlim2 in podocytes of patients with minimal change nephrotic syndrome and membranous nephropathy, whereas its expression was unchanged in patients with focal segmental glomerulosclerosis. Hence, pdlim2 is a novel actin-regulating protein of podocyte foot processes that may have a role in the pathogenesis of glomerular diseases.
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- Tersmeden, Fredrik, et al.
(författare)
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Hedna gudar i Herrens hus : Om promotionerna i domkyrkan och om dem som inte hölls där
- 2023
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Ingår i: Lunds domkyrka : Idéer och världsbilder - Idéer och världsbilder. - 0284-1894 .- 1401-1301. - 9789170614231 - 9789170614712 ; 8:245, s. 392-397
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Kort historisk betraktelse över domkyrkan som lokal för universitetets promotioner med fokus dels på inslaget av anspelningar på antik mytologi, dels på varför promotionerna under ett drygt halvsekel flyttades till andra lokaler.
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