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Renin cells with defective Gsα/cAMP signaling contribute to renal endothelial damage

  • Organ physiology
  • Published:
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A Commentary to this article was published on 08 August 2019

Abstract

Synthesis of renin in renal renin-producing cells (RPCs) is controlled via the intracellular messenger cAMP. Interference with cAMP-mediated signaling by inducible knockout of Gs-alpha (Gsα) in RPCs of adult mice resulted in a complex adverse kidney phenotype. Therein, glomerular endothelial damage was most striking. In this study, we investigated whether Gsα knockout leads to a loss of RPCs, which itself may contribute to the endothelial injury. We compared the kidney phenotype of three RPC-specific conditional mouse lines during continuous induction of recombination. Mice expressing red fluorescent reporter protein tdTomato (tdT) in RPCs served as controls. tdT was also expressed in RPCs of the other two strains used, namely with RPC-specific Gsα knockout (Gsα mice) or with RPC-specific diphtheria toxin A expression (DTA mice, in which the RPCs should be diminished). Using immunohistological analysis, we found that RPCs decreased by 82% in the kidneys of Gsα mice as compared with controls. However, the number of tdT-positive cells was similar in the two strains, demonstrating that after Gsα knockout, the RPCs persist as renin-negative descendants. In contrast, both renin-positive and tdT-labeled cells decreased by 80% in DTA mice suggesting effective RPC ablation. Only Gsα mice displayed dysregulated endothelial cell marker expression indicating glomerular endothelial damage. In addition, a robust induction of genes involved in tissue remodelling with microvascular damage was identified in tdT-labeled RPCs isolated from Gsα mice. We concluded that Gsα/renin double-negative RPC progeny essentially contributes for the development of glomerular endothelial damage in our Gsα-deficient mice.

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Acknowledgments

The competent technical assistance of Kathleen Fischer, Anika Lüdemann, and Nicole Bunk is gratefully acknowledged. We are greatly indebted to Lee S. Weinstein, Min Chen, and Jürgen Schnermann from NIH-NIDDK for providing transgenic mice. We thank the Light Microscopy Facility (Core Facility of the CMCB Technology Platform at Technical University, Dresden), the CFCI (Core Facility Cellular Imaging), the Institute of Clinical Chemistry (University Hospital Carl Gustav Carus, Dresden), and the Flow Cytometry Core Facility (Center for Molecular and Cellular Bioengineering, Technical University Dresden) for their support.

Data availability statement

The data generated or analyzed during this study are available from the corresponding author upon reasonable request.

Funding

This work was supported by Deutsche Forschungsgemeinschaft, grants TO 679/2-1, TO 679/3-1, HU 600/6-1, HU 600/8-1, and GE 2845/1-1, and the Graduate Academy of TU Dresden.

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Author notes

  1. Michael Gerlach

    Present address: Core Facility Cellular Imaging (CFCI), Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstraße 74, 01307, Dresden, Germany

  2. Peter Lachmann

    Present address: Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University Dresden, Fetscherstraße 74, 01307, Dresden, Germany

Authors and Affiliations

  1. Experimental Nephrology, Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany

    Anne Steglich, Friederike Kessel, Linda Hickmann, Michael Gerlach, Peter Lachmann, Florian Gembardt, Christian P. M. Hugo & Vladimir T. Todorov

  2. Dresden-concept Genome Center, c/o Center for Molecular and Cellular Bioengineering (CMCB), Technical University Dresden, Fetscherstr. 105, 01307, Dresden, Germany

    Mathias Lesche & Andreas Dahl

  3. Institute of Physiology, University of Regensburg, Universitätsstraße 31, 93053, Regensburg, Germany

    Anna Federlein & Frank Schweda

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Contributions

AS designed and performed experiments/microscopy, analyzed and interpreted data, and wrote and revised the manuscript; FK analyzed data and edited the manuscript; LH performed experiments, interpreted data, and edited the manuscript; MG performed microscopy and edited the manuscript; PL performed the experiments; FG edited the manuscript; ML analyzed the data; AD analyzed the data; AF and FS performed the experiments; CH interpreted data and edited the manuscript; VT conceived and designed the study, interpreted the data, and wrote and revised the manuscript.

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Correspondence to Vladimir T. Todorov.

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All animal experiments were performed in accordance with the Federal Law on the Use of Experimental Animals in Germany and were approved by the local authorities (Landesdirektion Sachsen). Animal experiments were consistent with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals (NIH Pub. No. 85-23, Revised 2011). This article does not contain any studies with human participants performed by any of the authors.

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Steglich, A., Kessel, F., Hickmann, L. et al. Renin cells with defective Gsα/cAMP signaling contribute to renal endothelial damage. Pflugers Arch - Eur J Physiol 471, 1205–1217 (2019). https://doi.org/10.1007/s00424-019-02298-9

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