A molecular mechanism explaining albuminuria in kidney disease

Butt, Linus; Unnersjö‐Jess, David; Höhne, Martin; Edwards, Aurélie; Binz-Lotter, Julia; Reilly, Dervla; Hahnfeldt, Robert; Ziegler, Vera; Fremter, Katharina; Rinschen, Markus M.; Helmstädter, Martin; Ebert, Lena; Castrop, Hayo; Hackl, Matthias J.; Walz, Gerd; Brinkkoetter, Paul T.; Liebau, Max C.; Tory, Kálmán; Hoyer, Peter F.; Beck, Bodo B.; Brismar, Hjalmar; Blom, Hans; Schermer, Bernhard; Benzing, Thomas

doi:10.1038/s42255-020-0204-y

Cited by 108 publications

(172 citation statements)

References 64 publications

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“…2 Along with the glomerular basement membrane, this fine membrane functions as a filtration barrier to prevent the passage of plasma proteins into the urinary filtrate. [3][4][5] Nephrin and Neph1 are known as the backbone proteins of the slit-diaphragm (SD) in podocytes. A failure to maintain these backbone proteins of the SD is believed to be the basis of proteinuria.…”

Section: Introductionmentioning

confidence: 99%

MAGI-2 orchestrates the localization of backbone proteins in the slit diaphragm of podocytes

Yamada

Shirata

Makino

et al. 2021

Kidney International

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Section: Introductionmentioning

confidence: 99%

MAGI-2 orchestrates the localization of backbone proteins in the slit diaphragm of podocytes

Yamada

Shirata

Makino

et al. 2021

Kidney International

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“…Assuming that the glomerular basement membrane is a compressible ultrafilter, 37 changes in the thickness of the glomerular filtration barrier are expected to have a direct impact on the total permeability of the filter. According to this theory, the pedicles of intact podocytes counteract the filtration pressure and decrease the permeability of the glomerular basement membrane 22,37 . Similarly, mesangial cells may contribute to the compression of the glomerular basement membrane in its basal aspect.…”

Section: Discussionmentioning

confidence: 99%

“…According to this theory, the pedicles of intact podocytes counteract the filtration pressure and decrease the permeability of the glomerular basement membrane. 22,37 Similarly, mesangial cells may contribute to the compression of the glomerular basement membrane in its basal aspect. Consequently, a loss of mesangial cells may lead to diminished compression and therefore to increased permeability of the glomerular basement membrane.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we hypothesized that contractile mesangial cells actively regulate glomerular haemodynamics and, consequently, are involved in the control of the single nephron glomerular filtration rate (snGFR). Furthermore, we hypothesized that mesangial cells may support the integrity of the glomerular filtration barrier, potentially by influencing the thickness and density of the glomerular basement membrane 22 . To test this hypothesis, we assessed the function of mesangial cells in vivo in Munich Wistar Froemter (MWF) rats using intravital multiphoton microscopy and ex vivo ultrastructural electron microscopy.…”

Section: Introductionmentioning

confidence: 99%

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Mesangial cells regulate the single nephron GFR and preserve the integrity of the glomerular filtration barrier: An intravital multiphoton microscopy study

et al. 2021

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Aim The intraglomerular mesangial cells are located between the glomerular capillaries. Here we hypothesized that mesangial cells regulate the single nephron glomerular filtration rate (snGFR) and that mesangial cells support the integrity of the glomerular filtration barrier. Methods We assessed the function of mesangial cells in vivo by multiphoton microscopy. Mesangial cells were depleted in Munich Wistar Froemter rats using the Thy1.1 antibody model. Results The Thy1.1 antibody caused the cell‐specific loss of 82 ± 3% of mesangial cells. After mesangial cell depletion, the baseline snGFR was reduced to 12.0 ± 1.2 vs 32.4 ± 3.2 nL/min in controls. In control rats, the snGFR decreased after angiotensin II infusion by 61 ± 3% (P = .004), whereas it remained unchanged in Thy1.1‐treated rats. The changes in the snGFR after angiotensin II infusion in control rats were accompanied by the marked rotation of the capillary loops within Bowman's space. This phenomenon was absent in anti‐Thy1.1‐treated rats. The glomerular sieving coefficient (GSCA) for albumin, used as a measure of the integrity of the glomerular filtration barrier, was low in control rats (0.00061 ± 0.00004) and increased after angiotensin II infusion (0.00121 ± 0.00015). In Thy1.1‐treated rats, the GSC was elevated (0.0032 ± 0.00059) and did not change in response to angiotensin II. Electron microscopy revealed the increased thickness of the glomerular basement membrane after mesangial cell depletion. Conclusion Our data suggest that mesangial cells actively contribute to the regulation of the snGFR. Furthermore, mesangial cells are crucially involved in maintaining the integrity of the glomerular filtration barrier, in part by modulating the thickness of the glomerular basement membrane.

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“…Similar to neurons, the glomerular epithelial cells, podocytes, are terminally differentiated cells that are not replaced post-development (Wanner et al, 2014). Podocytes are an integral part of the primary filtration unit of the kidney (Butt et al, 2020) and their loss is a leading causes of chronic kidney disease, such as diabetes, hypertension and glomerulopathies, with ensuing loss of protein into the urine (Chen et al, 2019). The precise pathomechanisms leading to podocyte depletion are incompletely understood, and treatments to better protect this finite number of cells are lacking (Rosenberg and Kopp, 2017).…”

Section: Introductionmentioning

confidence: 99%

Loss of genome maintenance accelerates podocyte damage and aging

Braun

Blomberg

Akbar-Haase

et al. 2020

Preprint

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DNA repair is essential for preserving genome integrity and ensures cellular functionality and survival. Podocytes have a very limited regenerative capacity, and their survival is essential to maintain kidney function. While podocyte depletion is a hallmark of glomerular diseases, the mechanisms leading to severe podocyte injury and loss remain largely unclear. We detected perturbations in DNA repair in biopsies from patients with various podocyte-related glomerular diseases and identified single-nucleotide polymorphisms associated with the expression of DNA repair genes in patients suffering from proteinuric kidney disease. Genome maintenance through nucleotide excision repair (NER) proved to be indispensable for podocyte homeostasis. Podocyte-specific knockout of the NER endonuclease co-factor Ercc1 resulted in accumulation of DNA damage, proteinuria, podocyte loss and glomerulosclerosis. The response to this genomic stress was fundamentally different to other cell types, as podocytes activate mTORC1 signaling upon DNA damage in vitro and in vivo.

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A molecular mechanism explaining albuminuria in kidney disease

Cited by 108 publications

References 64 publications

MAGI-2 orchestrates the localization of backbone proteins in the slit diaphragm of podocytes

MAGI-2 orchestrates the localization of backbone proteins in the slit diaphragm of podocytes

Mesangial cells regulate the single nephron GFR and preserve the integrity of the glomerular filtration barrier: An intravital multiphoton microscopy study

Loss of genome maintenance accelerates podocyte damage and aging

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