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Hypertension alters the function and expression profile of the peptide cotransporters PEPT1 and PEPT2 in the rodent renal proximal tubule

Abstract

Hypertension is a major risk factor for kidney and cardiovascular disease. The treatment of hypertensive individuals by selected ACE inhibitors and certain di-and tripeptides halts the progression of renal deterioration and extends life-span. Renal reabsorption of these low molecular weight substrates are mediated by the PEPT1 and PEPT2 cotransporters. This study aims to investigate whether hypertension and ageing affects renal PEPT cotransporters at gene, protein expression and distribution as well as function in the superficial cortex and the outer medulla of the kidney. Membrane vesicles from the brush border (BBMV) and outer medulla (OMMV) were isolated from the kidneys of young Wistar Kyoto (Y-WKY), young spontaneously hypertensive (Y-SHR), and middle aged SHR (M-SHR) rats. Transport activity was measured using the substrate, β-Ala-Lys (AMCA). Gene expression levels of PEPT genes were assessed with qRT-PCR while renal localisation of PEPT cotransporters was examined by immunohistochemistry with Western Blot validation. The Km and Vmax of renal PEPT1 were decreased significantly in SHR compared to WKY BBMV, whilst the Vmax of PEPT2 showed differences between SHR and WKY. By contrast to the reported cortical distribution of PEPT1, PEPT1-staining was detected in the outer medulla, whilst PEPT2 was expressed primarily in the cortex of all SHR; PEPT1 was significantly upregulated in the cortex of Y-SHR. These outcomes are indicative of a redistribution of PEPT1 and PEPT2 in the kidney proximal tubule under hypertensive conditions that has potential repercussions for nutrient handling and the therapeutic use of ACE inhibitors in hypertensive individuals.

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Acknowledgements

This work was supported by the Saudi Ministry of Higher Education, University of New England, and University of Jeddah. We would also like to thank Mr. Brian Cross and Mr. Jonathon Clay for their excellent technical assistance.

Funding

This work was supported by the Saudi Ministry of Higher Education, University of New England, and University of Jeddah.

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Contributions

OA performed the research, analysed the data and wrote the first draft of the paper. NK analysed the data and substantially edited the first draft. NA and BC and PW contributed methods to the paper and analysed the results. PM conceived the study and edited the final draft.

Corresponding author

Correspondence to Nicola King.

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This study was approved by the Animal Ethics committee of the University of New England, and complied with the Guide for the care and use of laboratory Animals published by the US National Institute of Health (NIH Publication No. 85–23, revised 1996).

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Alghamdi, O.A., King, N., Andronicos, N.M. et al. Hypertension alters the function and expression profile of the peptide cotransporters PEPT1 and PEPT2 in the rodent renal proximal tubule. Amino Acids 54, 1001–1011 (2022). https://doi.org/10.1007/s00726-022-03154-4

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  • DOI: https://doi.org/10.1007/s00726-022-03154-4

Keywords

  • Hypertension
  • PEPT1 and PEPT2
  • Ageing
  • Di- and tripeptides