Spatiotemporal organisation of protein processing in the kidney

Marcello Polesel, Monika Kaminska, Dominik Haenni, Milica Bugarski, Claus Schuh, Nevena Jankovic, Andres Kaech, Jose M. Mateos, Marine Berquez and Andrew M. Hall ()
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Marcello Polesel: University of Zurich
Monika Kaminska: University of Zurich
Dominik Haenni: University of Zurich
Milica Bugarski: University of Zurich
Claus Schuh: University of Zurich
Nevena Jankovic: University of Zurich
Andres Kaech: University of Zurich
Jose M. Mateos: University of Zurich
Marine Berquez: University of Zurich
Andrew M. Hall: University of Zurich

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract The kidney regulates plasma protein levels by eliminating them from the circulation. Proteins filtered by glomeruli are endocytosed and degraded in the proximal tubule and defects in this process result in tubular proteinuria, an important clinical biomarker. However, the spatiotemporal organization of renal protein metabolism in vivo was previously unclear. Here, using functional probes and intravital microscopy, we track the fate of filtered proteins in real time in living mice, and map specialized processing to tubular structures with singular value decomposition analysis and three-dimensional electron microscopy. We reveal that degradation of proteins requires sequential, coordinated activity of distinct tubular sub-segments, each adapted to specific tasks. Moreover, we leverage this approach to pinpoint the nature of endo-lysosomal disorders in disease models, and show that compensatory uptake in later regions of the proximal tubule limits urinary protein loss. This means that measurement of proteinuria likely underestimates severity of endocytotic defects in patients.

Date: 2022
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DOI: 10.1038/s41467-022-33469-5

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