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Renal retinol reabsorption is essential in tubular damage and regeneration

Renal retinol reabsorption is essential in tubular damage and regeneration. Jan Hinrich Bräsen , Philine Böckmann, Volker Maus, Melina Nieminen 1 , Duska Dragun 1 , Friedrich C. Luft 2 , Thomas Willnow 2 Institute for Pathology Christian-Albrechts-Universität Kiel,

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Renal retinol reabsorption is essential in tubular damage and regeneration

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  1. Renalretinolreabsorptionis essential in tubulardamageandregeneration Jan Hinrich Bräsen, Philine Böckmann, Volker Maus, Melina Nieminen1, Duska Dragun1, Friedrich C. Luft2, Thomas Willnow2 Institute forPathology Christian-Albrechts-Universität Kiel, 1Dept. forNephrology, Charité, and2Max Delbrück Center forMolecularMedicine, Berlin, Germany

  2. Background and Hypothesis • - low molecular retinol binding protein (RBP)–retinol complexes undergo free glomerular filtration and complete reabsoption by receptor-mediated endocytosis via Megalin in proximal renal tubuli (Christensen et al. JASN 1999) • - Vitamin D is finally hydroxylated during endo-lysosomal processing (Nykjaer et al. Cell 1999) • Does proximal tubular retinol deficiency influence renal tubular regeneration following ischemia-reperfusion injury?

  3. normal PTC injured PTC RBP-retinol RBP-retinol Megalin receptors Lysosomal processing disturbed expression of receptors loss of polarity EMT? normal expression of receptors regeneration differentiation polarity RAR-RXR RAR-RXR RARE RARE TGF-ß? TGF-ß? „anti -fibrosis“ inflammation / fibrosis?

  4. Methods • mouse model of renal tubular retinoid deficiency: • wild type (C57BL\6), RBP-KO, Megalin-KO (n=10 each) • 45 minutes ischemia by bilateral renal pedicle clamping • sacrifice at day 2 and 7 post reperfusion • renal function (creatinine level) • tubular damage scoring (debris, brush border, polarity, BM disruption) • immunohistochemistry (Ki67, CD3, FoxP3, TGF-b, ICAM-1)

  5. Ischemia-reperfusion damage in proximal renal tubuli: loss of polarity and reduced cytoplasmic RBP RBP Megalin

  6. Retinol deficiency aggravates tubular damage proximal tubular damage score 7d renal function * * * * * creatinine (mg/dl) wt Megalin RBP wt Megalin RBP 2d 7d number of tubuli / cross section RBP-KO wt Megalin-KO * p<0.01 compared to control and Megalin-KO

  7. Retinol deficiency aggravates tubular damage (7d) RBP-KO wt Megalin-KO

  8. Retinol deficiency inhibits tubular regeneration proliferation 2d proliferation 7d proliferation 2d P < 0.001 P < 0.01 Ki-67 - positive tubular cells / HPF Ki-67 - positive tubular cells / HPF control Megalin-KO RBP-KO wt wt Megalin-KO RBP-KO Megalin-KO

  9. Retinol deficiency inhibits tubular regeneration (Ki67, 7d) RBP-KO wt Megalin-KO

  10. Retinol deficiency reduces renal interstitial T-cell infiltration CD3 -positive T-cell infiltrates 7d CD3 -positive T-cell infiltrates 2d P < 0.01 P < 0.01 P < 0.05 P < 0.05 CD3 - positive cells / HPF CD3 - positive cells / HPF wt wt Megalin-KO RBP-KO Megalin-KO RBP-KO

  11. Retinol deficiency reduces renal interstitial T-cell infiltration (CD3, 7d) RBP-KO wt Megalin-KO

  12. Retinol deficiency reduces renal interstitial FoxP3-T-regs FoxP3 -positive T-reg infiltrates 2d FoxP3 -positive T-reg infiltrates 7d P < 0.01 P < 0.05 P < 0.05 FoxP3 - positive cells / cross section FoxP3 - positive cells / cross section wt wt Megalin-KO RBP-KO Megalin-KO RBP-KO

  13. Retinol deficiency reduces renal interstitial FoxP3+T-regs (FoxP3, 7d) RBP-KO wt Megalin-KO

  14. Retinol deficiency reduces renal tubular TGF-beta expression TGF-beta expression 2d TGF-beta expression 7d P < 0.05 P < 0.05 TGF-beta immunostained area (%) TGF-beta immunostained area (%) wt wt Megalin-KO RBP-KO Megalin-KO RBP-KO

  15. Retinol deficiency reduces renal tubular TGF-beta expression (TGF-b1, 7d) RBP-KO wt Megalin-KO

  16. Retinol deficiency and renal peritubular ICAM-1 expression ICAM-1 expression 2d ICAM-1 expression 7d ICAM-1 positive capillaries / HPF ICAM-1 positive capillaries / HPF wt wt Megalin-KO RBP-KO Megalin-KO RBP-KO

  17. Summary and Conclusion • Deficiency of renal tubular retinoid resorption • inhibits tubular regeneration following ischemia reperfusion • reduces CD3-positive T-cellinfiltration • reduces FoxP-3-positive T-regs • retinoidsmay open newtreatmentoptions in reperfusioninjuryandtransplantation

  18. Acknowledgements • Max Gottesman • Wolfgang Schneider • Bärbel Kuhlmann • Wolfram Klapper • Jan Sperveslage • Monika Stepanowski • Sylvia Iversen • Monika Hauberg • Maike Pacena

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