Sensing of tubular flow and renal electrolyte transport

Abstract

The kidney is a remarkable organ that accomplishes the challenge of removing waste from the body and simultaneously regulating electrolyte and water balance. Pro-urine flows through the nephron in a highly dynamic manner and adjustment of the reabsorption rates of water and ions to the variable tubular flow is required for electrolyte homeostasis. Renal epithelial cells sense the tubular flow by mechanosensation. Interest in this phenomenon has increased in the past decade since the acknowledgement of primary cilia as antennae that sense renal tubular flow. However, the significance of tubular flow sensing for electrolyte handling is largely unknown. Signal transduction pathways regulating flow-sensitive physiological responses involve calcium, purinergic and nitric oxide signalling, and are considered to have an important role in renal electrolyte handling. Given that mechanosensation of tubular flow is an integral role of the nephron, defective tubular flow sensing is probably involved in renal disease. Studies investigating tubular flow and electrolyte transport differ in their methodology, subsequently hampering translational validity. This Review provides the basis for understanding electrolyte disorders originating from altered tubular flow sensing as a result of pathological conditions.

Key points

  • Renal tubular flow is highly variable owing to the glomerular filtration rate, tubuloglomerular feedback, renal pelvic wall contraction and fluid reabsorption along the nephron.

  • To regulate water and electrolyte balance, adjustment of water and electrolyte reabsorption rates is required according to the variable tubular flow.

  • Renal epithelial cells contain specialized sensing machinery that transduces changes in tubular flow into a cellular response that regulates water and electrolyte transport.

  • Tubular flow regulates renal water and electrolyte transport along the different segments of the nephron.

  • Discerning how renal water and electrolyte handling is affected by tubular flow is essential in understanding how aberrant tubular flow sensing could result in pathophysiological conditions.

  • Improved understanding of renal tubular flow dynamics will aid the development of novel therapeutic options for diseases related to tubular flow sensing.

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Fig. 1: Flow-sensing machinery in the kidney.
Fig. 2: Mechanosensitive signalling pathways affecting electrolyte reabsorption.
Fig. 3: Urinary flow sensing and electrolyte transport along the nephron.
Fig. 4: Schematic overview of tubular flow characteristics in the kidney.

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Acknowledgements

The work of the authors is supported by grants from the Dutch Kidney Foundation (15OP03) to R.J.M.B. and D.J.M.P., and from the Netherlands Organization for Scientific Research (NWO VICI 016.130.668) to J.G.J.H.

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Glossary

Tubuloglomerular feedback

Feedback mechanism to regulate glomerular filtration rate involving the macula densa.

Mechanosensation

Response mechanism to mechanical stimuli.

Fluid shear stress

Measure of the resistance to fluid movement, related to the fluid viscosity.

Circumferential stretch

Stretch of renal epithelial cells lining the tubular lumen.

Microvilli

Plasma membrane extensions that increase the surface area.

Primary cilium

Single non-motile cilium that lacks a central pair of microtubules.

Autocrine activation

Signalling mechanism in which a secreted molecule of a cell binds to a receptor on that same cell.

Paracrine activation

Signalling mechanism in which a secreted molecule of a cell binds to a receptor on another cell.

G protein-coupled receptors

Protein family of receptors capable of detecting molecules extracellularly and in turn activating signalling pathways intracellularly.

Microperfusion

Technique to study tubular cell function in perfused isolated renal tubules.

Micropuncture

Technique to study single nephron function in the intact kidney.

Patch clamp technique

Technique in electrophysiology to study ion channel characteristics in isolated living cells.

Microfluidics

Technique that mimics, in miniature scale, the behaviour of fluids in order to study the effect of fluid flow on a target tissue; this technique is especially applied in organ-on-a-chip technology.

Oscillatory turbulent flow

Flow of fluid in an irregular motion in both direction and magnitude.

Unidirectional laminar flow

Flow of fluid in a regular motion with a constant direction.

Organoids

Miniaturized versions of an organ, produced in vitro in 3D.

Kidney-on-a-chip technology

In vitro system mimicking the 3D microenvironment of the kidney.

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Verschuren, E.H.J., Castenmiller, C., Peters, D.J.M. et al. Sensing of tubular flow and renal electrolyte transport. Nat Rev Nephrol 16, 337–351 (2020). https://doi.org/10.1038/s41581-020-0259-8

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