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Spatiotemporal Landscape of Kidney Tubular Responses to Glomerular Proteinuria


Faivre, Anna; Bugarski, Milica; Rinaldi, Anna; Sakhi, Imene B; Verissimo, Thomas; Legouis, David; Correia, Sara; Kaminska, Monika; Dalga, Delal; Malpetti, Daniele; Cippa, Pietro E; de Seigneux, Sophie; Hall, Andrew M (2024). Spatiotemporal Landscape of Kidney Tubular Responses to Glomerular Proteinuria. Journal of the American Society of Nephrology (JASN), 35(7):854-869.

Abstract

BACKGROUND

Large increases in glomerular protein filtration induce major changes in body homeostasis and increase risk of kidney functional decline and cardiovascular disease. We investigated how elevated protein exposure modifies the landscape of tubular function along the entire nephron, to understand the cellular changes that mediate these important clinical phenomena.

METHODS

We conducted single nuclei RNA sequencing, functional intravital imaging, and antibody staining to spatially map transport processes along the mouse kidney tubule. We then delineated how these were altered in a transgenic mouse model of inducible glomerular proteinuria (POD-ATTAC) at 7 and 28 days.

RESULTS

Glomerular proteinuria activated large-scale and pleotropic changes in gene expression in all major nephron sections. Extension of protein uptake from early (S1) to later (S2) parts of the proximal tubule initially triggered dramatic expansion of a hybrid S1/2 population, followed by injury and failed repair, with the cumulative effect of loss of canonical S2 functions. Proteinuria also induced acute injury in S3. Meanwhile, overflow of luminal proteins to the distal tubule caused transcriptional convergence between specialized regions and generalized dedifferentiation.

CONCLUSIONS

Proteinuria modulated cell signaling in tubular epithelia and causes distinct patterns of remodeling and injury in a segment specific manner.

Abstract

BACKGROUND

Large increases in glomerular protein filtration induce major changes in body homeostasis and increase risk of kidney functional decline and cardiovascular disease. We investigated how elevated protein exposure modifies the landscape of tubular function along the entire nephron, to understand the cellular changes that mediate these important clinical phenomena.

METHODS

We conducted single nuclei RNA sequencing, functional intravital imaging, and antibody staining to spatially map transport processes along the mouse kidney tubule. We then delineated how these were altered in a transgenic mouse model of inducible glomerular proteinuria (POD-ATTAC) at 7 and 28 days.

RESULTS

Glomerular proteinuria activated large-scale and pleotropic changes in gene expression in all major nephron sections. Extension of protein uptake from early (S1) to later (S2) parts of the proximal tubule initially triggered dramatic expansion of a hybrid S1/2 population, followed by injury and failed repair, with the cumulative effect of loss of canonical S2 functions. Proteinuria also induced acute injury in S3. Meanwhile, overflow of luminal proteins to the distal tubule caused transcriptional convergence between specialized regions and generalized dedifferentiation.

CONCLUSIONS

Proteinuria modulated cell signaling in tubular epithelia and causes distinct patterns of remodeling and injury in a segment specific manner.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
04 Faculty of Medicine > University Hospital Zurich > Clinic for Nephrology
04 Faculty of Medicine > Zurich Kidney Center (ZKC)
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:1 July 2024
Deposited On:08 May 2024 12:53
Last Modified:02 Jul 2024 01:05
Publisher:American Society of Nephrology
ISSN:1046-6673
OA Status:Closed
Publisher DOI:https://doi.org/10.1681/ASN.0000000000000357
PubMed ID:38652545