Project P5

Genetic mutations in proteins of the nuclear pore complex (NPC) cause podocytopathy and -loss resulting in focal and segmental glomerulosclerosis (FSGS) and chronic kidney disease (CKD). NPCs are huge protein complexes in the nuclear envelope that regulate the transport and distribution of proteins in the nucleoplasm versus the cytoplasm by both functionating as essential transport gate and permeability barrier.

The podocyte is a critical cell in the kidney, which cannot be replaced as it does not divide. In most glomerular diseases as well as in physiological aging, podocytes are lost for yet unknown reasons. Here we explore whether an impaired NPC function leading to protein mislocalization can explain the loss of podocytes in physiological aging and in glomerular disease. For this, we analyze the nuclear versus cytoplasmic distribution of podocyte proteins in aged mice and in a rat strain with a genetic form of FSGS. We develop methods to manipulate protein distribution between the nucleus and cytoplasm to restore defective nuclear/cytoplasmic compartmentalization in biochemical and cellular assays as well as animal models.

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Kuppe C, Leuchtle K, Wagner A, Kabgani N, Saritas T, Puelles VG, Smeets B, Hakroush S, van der Vlag J, Boor P, Schiffer M, Gröne HJ, Fogo A, Floege J, Moeller MJ. Novel parietal epithelial cell subpopulations contribute to focal segmental glomerulosclerosis and glomerular tip lesions. Kidney Int 2019 96: 80-93

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Puelles VG, Fleck D, Ortz L, Papadouri S, Strieder T, Böhner AMC, van der Wolde JW, Vogt M, Saritas T, Kuppe C, Fuss A, Menzel S, Klinkhammer BM, Müller-Newen G, Heymann F, Decker L, Braun F, Kretz O, Huber TB, Susaki EA, Ueda HR, Boor P, Floege J, Kramann R, Kurts C, Bertram JF, Spehr M, Nikolic-Paterson DJ, Moeller MJ. Novel 3D analysis using optical tissue clearing documents the evolution of murine rapidly progressive glomerulonephritis. Kidney Int 2019 96: 505-516

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Lazareth H, Henique C, Lenoir O, Puelles VG, Flamant M, Bollée G, Fligny C, Camus M, Guyonnet L, Millien C, Gaillard F, Chipont A, Robin B, Fabrega S, Dhaun N, Camerer E, Kretz O, Grahammer F, Braun F, Huber TB, Nochy D, Mandet C, Bruneval P, Mesnard L, Thervet E, Karras A, Le Naour F, Rubinstein E, Boucheix C, Alexandrou A, Moeller MJ, Bouzigues C, Tharaux PL. The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression. Nat Commun 10 2019: 3303

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Braun DA, Lovric S, Schapiro D, Schneider R, Marquez J, Asif M, Hussain MS, Daga A, Widmeier E, Rao J, Ashraf S, Tan W, Lusk CP, Kolb A, Jobst-Schwan T, Schmidt JM, Hoogstraten CA, Eddy K, Kitzler TM, Shril S, Moawia A, Schrage K, Khayyat AIA, Lawson JA, Gee HY, Warejko JK, Hermle T, Majmundar AJ, Hugo H, Budde B, Motameny S, Altmüller J, Noegel AA, Fathy HM, Gale DP, Waseem SS, Khan A, Kerecuk L, Hashmi S, Mohebbi N, Ettenger R, Serdaroğlu E, Alhasan KA, Hashem M, Goncalves S, Ariceta G, Ubetagoyena M, Antonin W, Baig SM, Alkuraya FS, Shen Q, Xu H, Antignac C, Lifton RP, Mane S, Nürnberg P, Khokha MK, Hildebrandt F. Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. J Clin Invest 2018 128: 4313-4328

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Braun DA, Sadowski CE, Kohl S, Lovric S, Astrinidis SA, Pabst WL, Gee HY, Ashraf S, Lawson JA, Shril S, Airik M, Tan W, Schapiro D, Rao J, Choi WI, Hermle T, Kemper MJ, Pohl M, Ozaltin F, Konrad M, Bogdanovic R, Büscher R, Helmchen U, Serdaroglu E, Lifton RP, Antonin W, Hildebrandt F. Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome. Nat Genet 2016 48: 457-65