Functional role of the renal risk gene WDR37 in renal disease
Final Report Abstract
Chronic kidney disease is the tenth leading cause of death worldwide. 10-15 % of the population are affected by chronic kidney disease. Chronic kidney disease causes renal failure in a subset of patients, necessitating kidney transplantation or dialysis. Common causes of chronic kidney disease are diabetes, auto-immune disease, hypertension or inherited syndromes, yet in 30-40 % the cause is unclear. To improve the understanding of the mechanisms underlying kidney diseases, risk genes for decreased renal funcion have been tabulated in large genomewide association studies. We have independently identified one of these genes, WDR37, as an interactor of LKB1, a metabolic sensor required for the normal architecture and function of the kidney. The function of WDR37 has been unknown. In this project, we investigated the function of WDR37 and found that WDR37 is associated with renal pathology. The search for interactors identified OPA1, a mitochondrial protein. Mitochondria produce cellular energy and respond to changes in energetic demands through fusion and fission. OPA1 is one of 3 proteins that regulate mitochondrial fusion. We found that loss of WDR37 stabilizes OPA1 at mitochondria and enhances their fusion. This alters mitochondrial architecture and function. In kidney cells, the loss of WDR37 leads to damaged mitochondria, secretion of pro-inflammatory molecules and increased cell death. This function explains how genetic changes in WDR37 may lead to a higher risk of chronic kidney disease.
Publications
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Identification of pathological transcription in autosomal dominant polycystic kidney disease epithelia. Scientific Reports, 11(1).
Friedrich, Sebastian; Müller, Hannah; Riesterer, Caroline; Schüller, Hannah; Friedrich, Katja; Wörner, Carlotta Leonie; Busch, Tilman; Viau, Amandine; Kuehn, E. Wolfgang; Köttgen, Michael & Hofherr, Alexis
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Ift88, but not Kif3a, is required for establishment of the periciliary membrane compartment. Biochemical and Biophysical Research Communications, 584, 19-25.
Kotsis, Fruzsina; Janusch, Heike; Li, Yujie; Viau, Amandine; Epting, Daniel; Kramer-Zucker, Albrecht; Walz, Gerd; Nitschke, Roland; Lorentzen, Esben; Ganner, Athina; Neumann-Haefelin, Elke; Kuehn, E. Wolfgang & Boehlke, Christopher
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Deutsche Gesellschaft für Nephrologie, Jahreskongress 2022, Berlin (8.10.22): eingeladener Vortrag: The role of inflammation in ADPKD and renal ciliopathies.
Wolfgang Kühn
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FASEB Meeting Polycystic Kidney Disease, Lisabon, Portugal (27.07.22) Eingeladener Vortrag: Inflammation and macrophages in renal ciliopathies
Wolfgang Kühn
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The renal inflammatory network of nephronophthisis. Human Molecular Genetics, 31(13), 2121-2136.
Quatredeniers, Marceau; Bienaimé, Frank; Ferri, Giulia; Isnard, Pierre; Porée, Esther; Billot, Katy; Birgy, Eléonore; Mazloum, Manal; Ceccarelli, Salomé; Silbermann, Flora; Braeg, Simone; Nguyen-Khoa, Thao; Salomon, Rémi; Gubler, Marie-Claire; Kuehn, E. Wolfgang; Saunier, Sophie & Viau, Amandine
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Tuning the 3D microenvironment of reprogrammed tubule cells enhances biomimetic modeling of polycystic kidney disease. Biomaterials, 291, 121910.
Pichler, Roman; Rizzo, Ludovica; Tröndle, Kevin; Bühler, Michaela; Brucker, Hanna; Müller, Anna-Lena; Grand, Kelli; Farè, Silvia; Viau, Amandine; Kaminski, Michael M.; Kuehn, E. Wolfgang; Koch, Fritz; Zimmermann, Stefan; Koltay, Peter & Lienkamp, Soeren S.
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TermineR: Extracting information on endogenous proteolytic processing from shotgun proteomics data. PROTEOMICS, 24(19).
Cosenza‐Contreras, Miguel; Seredynska, Adrianna; Vogele, Daniel; Pinter, Niko; Brombacher, Eva; Cueto, Ruth Fiestas; Dinh, Thien‐Ly Julia; Bernhard, Patrick; Rogg, Manuel; Liu, Junwei; Willems, Patrick; Stael, Simon; Huesgen, Pitter F.; Kuehn, E. Wolfgang; Kreutz, Clemens; Schell, Christoph & Schilling, Oliver
