The transcription factor ATF4 mediates endoplasmic reticulum stress-related podocyte injury and slit diaphragm defects

Krausel, Vanessa; Pund, Lisanne; Nüsse, Harald; Bachir, Hussein; Ricker, Andrea; Klingauf, Jürgen; Weide, Thomas; Pavenstädt, Hermann; Krahn, Michael P.; Braun, Daniela A.

doi:10.1016/j.kint.2022.11.024

Cited by 3 publications

(1 citation statement)

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“…This was accompanied by a dramatic upregulation in the activity of ATF4 (Fig. 7x–z ), a stress responsive transcription factor implicated in the integrated stress response (ISR) 76 and recently suggested to drive cellular injury in human renal cells 77 . Intriguingly, age-associated metabolic inefficiency has recently been shown to trigger the ISR and cause ‘hyper-metabolism’ due to the enormous energetic cost of mounting these wide-scale stress responses 65 .…”

Section: Resultsmentioning

confidence: 90%

Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing

Holcombe,

Weavers

2023

Nat Commun

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Precise coupling between cellular physiology and metabolism is emerging as a vital relationship underpinning tissue health and longevity. Nevertheless, functional-metabolic coupling within heterogenous microenvironments in vivo remains poorly understood due to tissue complexity and metabolic plasticity. Here, we establish the Drosophila renal system as a paradigm for linking mechanistic analysis of metabolism, at single-cell resolution, to organ-wide physiology. Kidneys are amongst the most energetically-demanding organs, yet exactly how individual cell types fine-tune metabolism to meet their diverse, unique physiologies over the life-course remains unclear. Integrating live-imaging of metabolite and organelle dynamics with spatio-temporal genetic perturbation within intact functional tissue, we uncover distinct cellular metabolic signatures essential to support renal physiology and healthy ageing. Cell type-specific programming of glucose handling, PPP-mediated glutathione regeneration and FA β-oxidation via dynamic lipid-peroxisomal networks, downstream of differential ERR receptor activity, precisely match cellular energetic demands whilst limiting damage and premature senescence; however, their dramatic dysregulation may underlie age-related renal dysfunction.

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Section: Resultsmentioning

confidence: 90%

Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing

Holcombe,

Weavers

2023

Nat Commun

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Insights into human kidney function from the study of Drosophila

Koehler

Huber

2023

Pediatr Nephrol

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Biological and biomedical research using Drosophila melanogaster as a model organism has gained recognition through several Nobel prizes within the last 100 years. Drosophila exhibits several advantages when compared to other in vivo models such as mice and rats, as its life cycle is very short, animal maintenance is easy and inexpensive and a huge variety of transgenic strains and tools are publicly available. Moreover, more than 70% of human disease-causing genes are highly conserved in the fruit fly. Here, we explain the use of Drosophila in nephrology research and describe two kidney tissues, Malpighian tubules and the nephrocytes. The latter are the homologous cells to mammalian glomerular podocytes and helped to provide insights into a variety of signaling pathways due to the high morphological similarities and the conserved molecular make-up between nephrocytes and podocytes. In recent years, nephrocytes have also been used to study inter-organ communication as links between nephrocytes and the heart, the immune system and the muscles have been described. In addition, other tissues such as the eye and the reproductive system can be used to study the functional role of proteins being part of the kidney filtration barrier.

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