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The evolving complexity of the collecting duct renin–angiotensin system in hypertension

Abstract

The intrarenal renin–angiotensin system is critical for the regulation of tubule sodium reabsorption, renal haemodynamics and blood pressure. The excretion of renin in urine can result from its increased filtration, the inhibition of renin reabsorption by megalin in the proximal tubule, or its secretion by the principal cells of the collecting duct. Modest increases in circulating or intrarenal angiotensin II (ANGII) stimulate the synthesis and secretion of angiotensinogen in the proximal tubule, which provides sufficient substrate for collecting duct-derived renin to form angiotensin I (ANGI). In models of ANGII-dependent hypertension, ANGII suppresses plasma renin, suggesting that urinary renin is not likely to be the result of increased filtered load. In the collecting duct, ANGII stimulates the synthesis and secretion of prorenin and renin through the activation of ANGII type 1 receptor (AT1R) expressed primarily by principal cells. The stimulation of collecting duct-derived renin is enhanced by paracrine factors including vasopressin, prostaglandin E2 and bradykinin. Furthermore, binding of prorenin and renin to the prorenin receptor in the collecting duct evokes a number of responses, including the non-proteolytic enzymatic activation of prorenin to produce ANGI from proximal tubule-derived angiotensinogen, which is then converted into ANGII by luminal angiotensin-converting enzyme; stimulation of the epithelial sodium channel (ENaC) in principal cells; and activation of intracellular pathways linked to the upregulation of cyclooxygenase 2 and profibrotic genes. These findings suggest that dysregulation of the renin–angiotensin system in the collecting duct contributes to the development of hypertension by enhancing sodium reabsorption and the progression of kidney injury.

Key points

  • Renin-expressing cells are present in various components of the nephron, including the juxtaglomerular apparatus, glomeruli, proximal tubules, connecting tubules and collecting ducts.

  • Collecting duct-derived renin is stimulated by a number of factors, including angiotensin II, prostaglandin E2, bradykinin and vasopressin, which contribute to the paracrine control of sodium reabsorption in the distal nephron.

  • Binding of prorenin and renin to the prorenin receptor, expressed by collecting duct cells, enhances the formation of intratubular angiotensin II and promotes kidney fibrosis.

  • In models of angiotensin II-dependent hypertension, components of the renin–angiotensin system, including proximal tubule-derived angiotensinogen, collecting duct-derived renin and the prorenin receptor expressed in the collecting duct, together facilitate the sustained formation of intratubular angiotensin II and stimulation of profibrotic factors leading to kidney tubule damage.

  • Circulating renin that is filtered and not reabsorbed by megalin in the proximal tubule may also contribute to renin in the urine.

  • The renin–angiotensin system in the distal nephron is complex and not fully understood but seems to involve coordinated actions to regulate intrarenal and intratubular angiotensin II, sodium reabsorption, blood pressure and fluid–electrolyte homeostasis.

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Fig. 1: The regulation of renin in juxtaglomerular cells.
Fig. 2: The regulation of renin in the collecting ducts.
Fig. 3: The PRR and renin interactions in distal nephron segments enhance profibrotic pathways and the formation of intratubular ANGII.

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Acknowledgements

The authors’ work is funded by the NIH through the CoBRE, P30GM-103337 grant to L.G.N; and the DK104375, 1U54GM104940 and UL1TR001417 grants to M.C.P. The authors thank Nancy Busija (Department of Pharmacology, Tulane University, USA) for editorial assistance with the manuscript before submission.

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M.C.P., A.A.G. and B.V. researched data for the article. M.C.P., A.A.G. and L.G.N. participated in the discussion of the content, writing and revising the article and/or editing the manuscript before submission.

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Correspondence to Minolfa C. Prieto.

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Glossary

2K1C Goldblatt hypertension

The two-kidney, one-clip (2K1C) Goldblatt hypertensive rat is an experimental model for studying renovascular hypertension, whereby one renal artery is clipped to decrease renal blood flow, and the other kidney remains unaffected.

Antisense oligonucleotides

Short DNA or RNA molecules that regulate gene expression by blocking the transcription or translation of target genes.

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Prieto, M.C., Gonzalez, A.A., Visniauskas, B. et al. The evolving complexity of the collecting duct renin–angiotensin system in hypertension. Nat Rev Nephrol 17, 481–492 (2021). https://doi.org/10.1038/s41581-021-00414-6

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