Publish at 18.11.2019
Presentation
(Patho)physiology of proximal tubular cells of the kidney
Specialised epithelial cells constitute the dominant executors of tissue-specific physiological functions. In the kidney, our main organ of interest, there are a number of different epithelial cells organized in segments along the nephron, and we are particularly interested in the proximal tubules. Epithelial cells of the proximal tubules have a very active endolysosomal system, and this is because its main task is to reabsorb virtually all the proteins that are filtered by the glomerulus. For this, the apical brush borders are equipped with a dedicated protein uptake pathway, involving the multiligand receptors megalin and cubilin. Failure of this pathway results in low-molecular-weight proteinuria, which is a hallmark of proximal tubulopathies (e.g. cystinosis and Dent’s disease). Our recent research in Drosophila has introduced a novel mechanism for the control of apical protein uptake with strong implications for proximal tubular cells (Gleixner et al., 2014). Our findings propose that lysosomal mTOR signaling - a major nutrient sensing pathway that controls metabolic decisions from the lysosomal surface - regulates the expression of megalin as well as the morphogenesis of the apical surface. Therefore, we are studying how protein and lipid ligands from the tubular lumen can amplify a cycle of endocytosis and lysosome-to-nucleus signaling to satisfy the high metabolic needs of proximal tubular cells.
Targeting tubular albumin uptake as a renoprotective strategy
Glomerular injury can lead to an overload of the proximal tubules with proteins. Particularly damaging is the uptake of albumin, because albumin can carry toxic fatty acids inside the cells. Our recent identification of patients carrying biallelic mutations of cubilin (gene name : CUBN) as well as population-based studes on more common CUBN variants suggest that dysfunctional cubilin leads to chronic proteinuria with normal renal function. CUBN-associated proteinuria was featured by high percentage of albuminuria, suggesting that cubilin could indeed be the main albumin receptor in the proximal tubules. Based on these findings, we propose that the targeting of cubilin could be a safe strategy in conditions with glomerular proteinuria, such as diabetic kidney disease (Simons, 2018 ; Bedin et al, 2019).
Drosophila as a tool in human genetics
The understanding of human genetic diseases has been greatly improved by novel techniques, such as next generation sequencing, allowing the complete genotyping of vast numbers of affected individuals and their relatives. Moreover, novel genome editing methods and reprogramming of patient-derived cells have enhanced the possibilities for functional follow-up studies. However, the evaluation of the pathogenicity of genetic variants remains a major bottleneck, because the human genome still lacks important functional gene information. An important goal of the lab is to employ the Drosophila model as an innovative toolkit for the rapid identification of novel genes for hereditary diseases, particularly in the area of kidney disease.
Team
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Matias Simons
Lab Director
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Luigi De La Motte
Post-doc
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Gwenn Le Meur
Engineer
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Zvonimir Marelja
Post-doc
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Albert Pérez Martí
Post-doc
Resources & publications
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J. Clin. Invest. 2019
Human C-terminal CUBN variants associate with chronic proteinuria and normal ...
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J. Am. Soc. Nephrol. 2019
The Benefits of Tubular Proteinuria: An Evolutionary Perspective.
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J. Med. Genet. 2019
De novo SCAMP5 mutation causes a neurodevelopmental disorder with autistic fe...
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J. Am. Soc. Nephrol. 2019
Filling the Gap: Drosophila Nephrocytes as Model System in Kidney Research.
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Nat. Methods 2019
U-Net: deep learning for cell counting, detection, and morphometry.
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Mol. Biol. Cell 2019
ATP6AP2 functions as a V-ATPase assembly factor in the endoplasmic reticulum.
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Wound Repair Regen 2018
Vacuolar ATPase is required for ERK-dependent wound healing in the Drosophila...
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Cell Tissue Res. 2018
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J. Clin. Invest. 2017
Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis an...
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J. Am. Soc. Nephrol. 2017
Targeting mTOR Signaling Can Prevent the Progression of FSGS.
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J. Am. Soc. Nephrol. 2017
Renal Atp6ap2/(Pro)renin Receptor Is Required for Normal Vacuolar H+-ATPase F...
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J. Am. Soc. Nephrol. 2017
APOL1-Mediated Cell Injury Involves Disruption of Conserved Trafficking Proce...
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Am. J. Hum. Genet. 2017
Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome.
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Mol. Biol. Cell 2016
Spontaneous and electric field-controlled front-rear polarization of human ke...
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J. Invest. Dermatol. 2015
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Dis Model Mech 2013
Elevated expression of the V-ATPase C subunit triggers JNK-dependent cell inv...

Research: a scientific adventure
Our goal: to better understand genetic diseases to better treat them.

Key numbers
Kidney research Proximal tubules
Cell biology endocytosis
metabolism lipid metabolism