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Tubuloglomerular Feedback Synchronization Occurs Across the Nephrovascular Network
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- Author / Creator
- Zehra, Tayyaba
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Renal autoregulation, comprised of the myogenic response (MR) and the kidney-specific tubuloglomerular feedback (TGF), maintains steady perfusion to the kidneys despite blood pressure fluctuations. The emphasis of this work is on TGF, the dynamics of which generate autonomous oscillations that synchronize extensively across the kidney. Synchronization occurs through endothelial gap junctions formed by connexin40 (Cx40) proteins which allow a nephrovascular unit (NVU), consisting of the nephron, glomerulus, afferent arteriole and efferent arteriole, to communicate electrically over long distances upstream to other NVUs via the vascular tree. Clusters of NVUs form dynamic small-world networks across the kidney, meaning that NVUs are tightly connected to each other in one cluster, but clusters are loosely interconnected to each other. Synchronization, or coupling, between NVUs spatiotemporally optimizes blood flow distribution to ensure that NVUs receive appropriate perfusion to match the energy-intensive and oxygen-dependent reabsorption of sodium.
Many patients with diabetes mellitus or hypertension have chronic kidney disease (CKD) secondary to their conditions. In Canada, recent estimates suggest that 4 million people suffer from CKD; this is associated with a health burden upwards of $40 billion per year 1. Loss of synchronization impairs autoregulation and is implicated in the progression of kidney disease, but synchronization has not been studied in pathophysiological models. We hypothesized that improving synchronization may preserve renal function by improving network behavior.
To advance our understanding of the nephrovascular network’s role in physiology with clinical relevance, we explored the impact of manipulating TGF signaling on synchronization in our first aim. In healthy male Lewis rats (n = 6), we inhibited the sensor component of the TGF to study synchronization and network behavior using acute administration of the loop diuretic furosemide. The sodium glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin was acutely administered in healthy rats (n = 6) to enhance TGF signaling by increasing sodium chloride delivery to the macula densa cells in the distal tubule.
In the second aim, we tested the impact of renal disease on TGF synchronization and network behavior using the remnant kidney model of experimental CKD to gain greater insight into the nephrovascular network’s role in pathophysiology. Male Lewis rats were subjected to 5/6th nephrectomy or sham-operations and were assessed after 1 week (n = 4) or 6 weeks (n = 6) (n = 7, 1 week shams; n = 7, 6 week shams).
Our third aim was to determine whether the SGLT2 inhibitor dapagliflozin would enhance synchronization in the pathophysiological context of experimental CKD. We used male Lewis rats that were subjected to 5/6th nephrectomy to create a remnant kidney for 6 weeks (n = 6) or sham operations (n = 6). After 6 weeks had elapsed, animals were acutely administered dapagliflozin.
In all three aims, laser speckle contrast imaging (LSCI) was used to assess renal cortical perfusion and determine the strength and variability in the synchronization of TGF and MR, the decay in TGF synchronization over distance, and the spatiotemporal heterogeneity of cortical perfusion.
Our results demonstrate furosemide induced a rapid decay in TGF synchronization over long distances, whereas dapagliflozin improved entrainment of regions across the renal surface in intact rats. Disruption of the nephrovascular network in the remnant kidney at 1 week enhanced MR synchronization, and at 6 weeks TGF synchronization and the maximum distance over which synchronization occurs was diminished. Breaking the network impaired the communication pathway necessary for TGF signals to travel because the remnant kidney at both 1 and 6 weeks induced a rapid decay in the spread of the TGF signal, reduced synchronization amongst kidney regions and induced heterogeneity in cortical perfusion. Intervention with dapagliflozin improved the strength of TGF synchronization and reduced the magnitude of its decay with distance, suggesting these changes may underlie SGLT2 inhibition’s renoprotective effects. These findings suggest that TGF is best regarded as a distributed network process that regulates the microcirculation by synchronized adjustments in vascular resistance amongst communicating NVUs so that all elements in the network effectively respond to blood pressure perturbations. The implications of these findings includes a greater understanding of nephrovascular network regulation that can be enhanced by intervention to restore coordinated vascular responses among NVUs with better oxygenation/perfusion matching and prevention of renal injury as a consequence.
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- Graduation date
- Fall 2020
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- Type of Item
- Thesis
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- Degree
- Master of Science
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- License
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