Journal of Biological Chemistry
Volume 295, Issue 40, 2 October 2020, Pages 13711-13723
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Metabolism
Dipeptidyl peptidase 3 modulates the renin–angiotensin system in mice

https://doi.org/10.1074/jbc.RA120.014183Get rights and content
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Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent hydrolase involved in degrading oligopeptides with 4–12 amino acid residues. It has been associated with several pathophysiological processes, including blood pressure regulation, pain signaling, and cancer cell defense against oxidative stress. However, the physiological substrates and the cellular pathways that are potentially targeted by DPP3 to mediate these effects remain unknown. Here, we show that global DPP3 deficiency in mice (DPP3−/−) affects the renin–angiotensin system (RAS). LC–MS–based profiling of circulating angiotensin peptides revealed elevated levels of angiotensin II, III, IV, and 1–5 in DPP3−/− mice, whereas blood pressure, renin activity, and aldosterone levels remained unchanged. Activity assays using the purified enzyme confirmed that angiotensin peptides are substrates for DPP3. Aberrant angiotensin signaling was associated with substantially higher water intake and increased renal reactive oxygen species formation in the kidneys of DPP3−/− mice. The metabolic changes and altered angiotensin levels observed in male DPP3−/− mice were either absent or attenuated in female DPP3−/− mice, indicating sex-specific differences. Taken together, our observations suggest that DPP3 regulates the RAS pathway and water homeostasis by degrading circulating angiotensin peptides.

angiotensin II
dipeptidyl peptidase 3 (DPP3)
metalloprotease
mouse
oxidative stress
peptidase
renal physiology
renin angiotensin system
kidney function
sex-specific difference
reactive oxygen species (ROS)

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Author contributions—S. J., U. T., T. M., K. G., R. Z., and P. M. conceptualization; S. J., U. T., B. B., T. M., R. Z., and P. M. data curation; S. J., U. T., O. D., M. Poglitsch, B. B., M. Pollheimer, L. M. P., G. M., S. F., T. M., R. Z., and P. M. formal analysis; S. J., U. T., R. Z., and P. M. validation; S. J., U. T., O. D., M. Poglitsch, B. B., M. Pollheimer, L. M. P., G. M., S. F., T. M., K. G., R. Z., and P. M. investigation; S. J., U. T., M. Pollheimer, and P. M. visualization; S. J., U. T., O. D., M. Poglitsch, B. B., M. Pollheimer, S. F., T. M., K. G., R. Z., and P. M. methodology; S. J. and P. M. writing-original draft; S. J., U. T., R. Z., and P. M. writing-review and editing; U. T., R. Z., and P. M. supervision; K. G., R. Z., and P. M. resources; K. G. and P. M. funding acquisition; R. Z. and P. M. project administration; P. M. software.

Funding and additional information—This work was supported by Austrian Science Foundation Grant W901 (Doctoral Program “Molecular Enzymology”; to K. G., R. Z., and P. M.) and by the Interuniversity Program in Natural Sciences (to NAWI Graz).

Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.

Abbreviations—The abbreviations used are:

    DPP3

    dipeptidyl peptidase 3

    DPP3+/+

    DPP3 wild-type

    DPP3−/−

    DPP3-knockout

    RAS

    renin–angiotensin system

    Ang

    angiotensin

    ROS

    reactive oxygen species

    ITC

    isothermal titration calorimetry

    ACE

    angiotensin-converting enzyme

    ARE

    antioxidant response element

    CMV

    cytomegalovirus

    EE

    energy expenditure

    H2DCFDA

    2′,7′-dichlorodihydrofluorescein diacetate

    E2

    17β-estradiol.

These authors contributed equally to this work.