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Renal nerves and hypertension contribute to impaired proximal tubule megalin-mediated albumin uptake in renovascular hypertensive rats

Hypertension Research volume 48, pages 1491–1502 (2025)Cite this article

A Comment to this article was published on 04 March 2025

Abstract

Proteinuria, especially albuminuria, serves as an independent risk factor for progression in cardiovascular and renal diseases. Clinical and experimental studies have demonstrated that renal nerves contribute to renal dysfunction in arterial hypertension (AH). This study hypothesizes that renal nerves mediate the mechanisms of protein endocytosis by proximal tubule epithelial cells (PTEC) and glomerular function; with dysregulation of the renal nerves contributing to proteinuria in Wistar rats with renovascular hypertension (2-kidney, 1-clip model, 2K-1C). Reduced albumin uptake and increased internalization of endocytic receptor megalin in PTEC were found in both the clipped and contralateral kidneys of 2K-1C rats. Renal denervation (DNx) or hydralazine treatment restored these parameters. Moreover, DNx, but not hydralazine, reduced serum creatinine and recovered podocyte numbers in the contralateral kidney of 2K-1C rats. Thus, our data suggest that renal nerves and high arterial pressure contribute to decreased albumin reabsorption by cellular redistribution of megalin in PTEC, while renal nerves remarkably drive glomerular dysfunction in renovascular hypertension, independently of their effect on blood pressure.

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Acknowledgements

We acknowledge the expert technical assistance in histological sections preparation of Jacilene Barbosa from the multi-user facility of Infar-UNIFESP, and the English grammar revision of Dr. Alex Dayton from University of Minnesota.

Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)— Finance Code 001, by the São Paulo Research Foundation (FAPESP 2019/25295-0; 2022/11063-2) and by the Brazilian National Research Council (CNPq 406233/2018-7). ACV was a recipient of FAPESP scholarship (2020/02617-9). RRC and CTB are recipients of the CNPq productive research fellowship. And CCN was supported by CNPq: 46.5656/2014-5 (to CC-N); 30.9112/2021-4 (to CC-N), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro–FAPERJ: E-26/210.046/2023 (CC-N), E-26/200.900/2021 (to CC-N), Rio Network of Innovation in Nanosystems for Health (Nanohealth/FAPERJ): E-26/010.000983/2019 (CC-N).

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Authors and Affiliations

  1. Department of Physiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil

    A. C. Veiga, M. I. O. Milanez, R. S. Aires, Y. A. C. Moraes, R. R. Campos, C. T. Bergamaschi & E. E. Nishi

  2. Carlos Chagas Filho Biophysics Institute, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    R. P. Silva-Aguiar & C. Caruso-Neves

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  1. A. C. Veiga
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  2. R. P. Silva-Aguiar
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Veiga, A.C., Silva-Aguiar, R.P., Milanez, M.I.O. et al. Renal nerves and hypertension contribute to impaired proximal tubule megalin-mediated albumin uptake in renovascular hypertensive rats. Hypertens Res 48, 1491–1502 (2025). https://doi.org/10.1038/s41440-025-02100-7

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