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Abstract: FR-OR25

The Role of Renal Mechanotransduction in Blood Volume Sensing

Session Information

Category: Fluid, Electrolytes, and Acid-Base Disorders

  • 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

  • Hill, Rose Z., Scripps Research Institute Department of Molecular and Cellular Neuroscience, La Jolla, California, United States
  • Burquez, Sebastian, Scripps Research Institute Department of Molecular and Cellular Neuroscience, La Jolla, California, United States
  • Shirvan, Sepenta, Scripps Research Institute Department of Molecular and Cellular Neuroscience, La Jolla, California, United States
  • Miner, Jeffrey H., Washington University in St Louis School of Medicine, St Louis, Missouri, United States
  • Patapoutian, Ardem, Scripps Research Institute Department of Molecular and Cellular Neuroscience, La Jolla, California, United States
Background

The kidneys tightly control the composition of our internal environment to maintain homeostasis in the face of external variability. For example, the regulation of blood volume begins in the kidneys and is essential for vertebrate life in terrestrial environments where salt and water availability are unpredictable. Renin release by specialized juxtaglomerular cells of the kidney is the rate-limiting step in an essential hormonal cascade that modulates blood volume, filtration, and salt balance. For several decades, it was known that renin is released in response to a loss of mechanical cues triggered by relaxation of the afferent arteriole. However, the identity and physiological significance of the mechanosensor in these cells was unknown. Here we examine the expression, function, and requirement of force-gated ion channels in renal juxtaglomerular cells.

Methods

We use in situ hybridization and immunohistochemistry to characterize the localization of force-gated ion channels in the juxtaglomerular apparatus (JGA). We generated conditional knockout mouse lines targeting stromal progenitors, cells of renin lineage, and adult-inducible pericyte-like cells, encompassing both the mesangium and the renin-expressing JG cells. We then subjected male and female mice to measurements of RAAS pathways hormones, glomerular filtration rate, and systemic blood pressure. Additionally, we isolated glomeruli from the kidneys of transgenic mice and cultured primary renin-expressing and mesangial cells for whole cell voltage clamp electrophysiology in order to measure mechanically activated currents due to force-gated ion channels.

Results

We find that loss of mechanotransduction in renin-expressing JG cells perturbs renal function and RAAS under normal conditions and subcutaneous polyethylene glycol-evoked hypovolemia. Specifically, we observe that genetic loss of mechanotransduction enhances renin release and RAAS function and promotes glomerular hyperfiltration. Furthermore, we find that primary cultured renin-expressing and mesangial cells are mechanosensitive and express functional force-gated ion channels.

Conclusion

Our findings highlight the importance of mechanotransduction within the JGA to renal blood volume sensing and represent the first molecular and cellular characterization of JGA mechanosensitivity and the consequences of its loss in vivo.

Funding

  • Private Foundation Support