mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans

Puelles, Victor G.; Wolde, James W. van der; Wanner, Nicola; Scheppach, Markus W.; Cullen‐McEwen, Luise A.; Bork, Tillmann; Lindenmeyer, Maja T.; Gernhold, Lukas; Wong, Milagros; Braun, Fabian; Cohen, Clemens D.; Kett, Michelle M; Kuppe, Christoph; Kramann, Rafael; Saritas, Turgay; Roeyen, Claudia R. van; Moeller, Marcus J.; Tribolet, Leon; Rebello, Richard J.; Sun, Yu; Li, Jinhua; Müller‐Newen, Gerhard; Hughson, Michael D.; Hoy, Wendy E.; Person, Fermín; Wiech, Thorsten; Ricardo, Sharon D.; Kerr, Peter G.; Denton, Kate M.; Furic, Luc; Huber, Tobias B.; Nikolic‐Paterson, David J.; Bertram, John F.

doi:10.1172/jci.insight.99271

Cited by 72 publications

(96 citation statements)

References 67 publications

(83 reference statements)

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“…Lithium therapy to treat conditions such as bipolar disorders rarely causes proteinuria and minimal changes or FSGS lesions, which can resolve within weeks after stopping the drug 118 ; however, the mechanism is controversial 119,120 . Sirolimus, doxorubicin and daunomycin can each cause a podocytopathy with FSGS lesions by directly inducing podocyte death [121][122][123] . Doxorubicin, used as a cancer chemotherapy in humans, is a podocyte toxin that is widely used to induce podocyte injury lesions in mice; it promotes mitotic catastrophe in podocytes, with consequent detachment, followed by FSGS lesions 124 .…”

Section: Pregnancy-related Vegf Inhibition Renal Physiological Changmentioning

confidence: 99%

Podocytopathies

Kopp

Anders

Suszták

et al. 2020

Nat Rev Dis Primers

253

226

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Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin-angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.

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Section: Pregnancy-related Vegf Inhibition Renal Physiological Changmentioning

confidence: 99%

Podocytopathies

Kopp

Anders

Suszták

et al. 2020

Nat Rev Dis Primers

253

226

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“…The second big group consisted of 8 genes related to an altered metabolism and might be a consequence of the podocytic attempts to morphologically adjust to loss of podocyte differentiation and number. Stress-related podocyte growth and hypertrophy is a well-known observation during FSGS also receiving a lot of attention recently [44,45].…”

Section: Plos Onementioning

confidence: 99%

Podocyte RNA sequencing reveals Wnt- and ECM-associated genes as central in FSGS

et al. 2020

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Loss of podocyte differentiation can cause nephrotic-range proteinuria and Focal and Segmental Glomerulosclerosis (FSGS). As specific therapy is still lacking, FSGS frequently progresses to end-stage renal disease. The exact molecular mechanisms of FSGS and gene expression changes in podocytes are complex and widely unknown as marker changes have mostly been assessed on the glomerular level. To gain a better insight, we isolated podocytes of miR-193a overexpressing mice, which suffer from FSGS due to suppression of the podocyte master regulator Wt1. We characterised the podocytic gene expression changes by RNAseq and identified many novel candidate genes not linked to FSGS so far. This included strong upregulation of the receptor tyrosine kinase EphA6 and a massive dysregulation of circadian genes including the loss of the transcriptional activator Arntl. By comparison with podocyte-specific changes in other FSGS models we found a shared dysregulation of genes associated with the Wnt signaling cascade, while classical podocyte-specific genes appeared widely unaltered. An overlap with gene expression screens from human FSGS patients revealed a strong enrichment in genes associated with extracellular matrix (ECM) and metabolism. Our data suggest that FSGS progression might frequently depend on pathways that are often overlooked when considering podocyte homeostasis.

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“…Podocytes are kidney epithelial cells with limited capacity for regeneration that function as master regulators of glomerular health 2 . Experimental models show that severe podocyte loss leads to an irreversible process of progressive scarring rendering the affected glomeruli non-functional 3–5 . Furthermore, human podocyte loss has been identified in association with all major diseases contributing to chronic kidney disease 6–13 .…”

Section: Introductionmentioning

confidence: 99%

“…While ANCA-GN has well-defined cellular changes 15 that include podocyte injury 16 , podocyte loss is yet to be characterized in ANCA-GN patients. Using indirect immunofluorescence imaging, it is now possible to visualize different podocyte structures, facilitating the unambiguous identification of podocytes and thereby quantification of podocyte depletion 5,6 . However, reliable image segmentation for routine clinical analysis remains challenging, mostly due to time-constraints for detailed quantitative analysis with cellular resolution and lack of accuracy in available automated methods.…”

Section: Introductionmentioning

confidence: 99%

Deep learning-based molecular morphometrics for kidney biopsies

Zimmermann

Klaus

Wong

et al. 2020

Preprint

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Morphologic examination of tissue biopsies is essential for histopathological diagnosis. However, accurate and scalable cellular quantification in human samples remains challenging. Here, we present a deep learning-based approach for antigen-specific cellular morphometrics in human kidney biopsies, which combines indirect immunofluorescence imaging with U-Net-based architectures for image-to-image translation and dual segmentation tasks, achieving human-level accuracy. In the kidney, podocyte loss represents a hallmark of glomerular injury and can be estimated in diagnostic biopsies. Thus, we profiled over 27,000 podocytes from 110 human samples, including patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN), an immune-mediated disease with aggressive glomerular damage and irreversible loss of kidney function. Previously unknown morphometric signatures of podocyte depletion were identified in patients with ANCA-GN, which allowed patient classification and showed potential for risk stratification in combination with routine clinical tools. Together, our approach enables robust and scalable molecular morphometric analysis of human tissues, yielding deeper biological insights into the human kidney pathophysiology.SummaryDeep learning enables robust and scalable molecular morphometric analysis of human tissues, yielding deeper biological insights into the human kidney pathophysiology.

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mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans

Cited by 72 publications

References 67 publications

Podocytopathies

Podocytopathies

Podocyte RNA sequencing reveals Wnt- and ECM-associated genes as central in FSGS

Deep learning-based molecular morphometrics for kidney biopsies

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