Anatomical and Optogenetic Investigations of Periglomerular Sensory Fibers in the Mouse Kidney
2022-06
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Anatomical and Optogenetic Investigations of Periglomerular Sensory Fibers in the Mouse Kidney
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2022-06
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Though sensory-specific renal denervation has been shown to lower blood pressure in some animal models of hypertension, indicating their importance in the development and maintenance of hypertension, the anatomical distribution and function of sensory renal nerve fibers have not been fully elucidated. Both the anatomical and physiological study of sensory renal nerves have previously focused on sensory nerves innervating the renal pelvis due to their density within the pelvis wall. However, previous studies have described the presence of sensory fibers in the renal cortex but did not quantitatively or functionally investigate this cortical innervation. To begin to address the question of the importance of sensory fibers in the renal cortex, I first used immunohistochemical, and tissue clearing techniques to quantitatively describe the anatomical relationship between sensory fibers and glomeruli. I showed that a majority of mouse renal glomeruli, regardless of their depth within the renal cortex, present with a nearby TRPV1+ or CGRP+ sensory fiber. High-resolution imaging of cleared tissue and three-dimensional distance transformation techniques revealed that sensory fibers travel within a few microns of the Nephrin+ signal of glomerular podocytes and come in close contact with multiple glomeruli that share a common interlobular artery. These anatomical results suggest that periglomerular sensory fibers may function in a mechanosensitive manner to monitor glomerular pressures. To attempt to determine their physiological function, I designed an optogenetic device that was implemented in an anesthetized mouse preparation to measure the effects of optogenetic stimulation of TRPV1+ cortical sensory fibers on cortical blood flow, mean arterial pressure, and renal vascular resistance. Additional experiments validated the ability of this preparation to detect expected changes in these measurements with the subcapsular injection of vasoactive substances, the presence of channelrhodopsin in cortical sensory fibers, the functionality of channelrhodopsin-containing TRPV1+ sensory fibers via optogenetic activation of the baroreflex, and the ability of our chosen light source to penetrate the depth of the renal cortex. Nonetheless, the method used for optogenetic stimulation of TRPV1+ fibers in the mouse renal cortex did not elicit significant changes in cortical blood flow, arterial pressure, or renal vascular resistance from baseline values. These inconclusive results indicate that either the TRPV1+ fibers were never sufficiently stimulated by the delivered light, or that their acute activation does not result in measurable short-term changes in the measured values. Taken together, the discovery of sensory fibers near most glomeruli and currently inconclusive results of a novel attempt to stimulate TRPV1+ cortical sensory fibers in a spatial, temporal, and subtype-specific manner indicates that our understanding of the anatomical distribution and function of sensory renal nerves requires additional investigation. A more thorough understanding of sensory renal nerve anatomy and function will also likely improve treatments for renal nerve-based diseases like hypertension.
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University of Minnesota Ph.D. dissertation. June 2022. Major: Neuroscience. Advisors: John Osborn, Lucy Vulchanova. 1 computer file (PDF); ix, 157 pages.
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Tyshynsky, Roman. (2022). Anatomical and Optogenetic Investigations of Periglomerular Sensory Fibers in the Mouse Kidney. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/241625.
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