Impact of changes in proximal tubular reabsorption on kidney function and on blood flow synchronization among nephrons
Creators: Poursharif, Shayan
Publisher: name: University of Alberta Library
Year: 2023

<p>Kidneys stabilize renal blood flow (RBF) in response to fluctuations in blood pressure by employing two mechanisms, the myogenic response (MR) and the tubuloglomerular feedback (TGF) mechanism. The TGF mechanism stabilizes macula densa solute delivery via controlling afferent arteriolar diameter. Furthermore, TGF generates oscillations within each nephrovascular unit (NVU), each nephron and its afferent and efferent arteriole, and oscillatory systems with similar frequencies can entrain and become synchronized.<br>
SGLT2 inhibitors can improve renal function in the early and advanced diabetic nephropathy by increasing macula densa solute delivery, activating the TGF mechanism and presumably improving synchronization among NVUs. Consequently, enhancing synchronization among NVUs by activating the TGF mechanism might improve renal hemodynamics and preserve renal function in diabetic nephropathy and non-diabetic chronic kidney disease (CKD). This is prominent as more than 3 million Canadians are suffering from CKD [1], which puts a great financial burden on the health care system. We used different compounds that could change TGF activity to understand synchronization among NVUs better and to see how the synchronization among NVUs would be affected.<br>
In our first aim, we tried to inhibit the sensing step of the TGF mechanism by administering high dose furosemide to assess synchronization among nearby NVUs in male Lewis rats (n=8). We hypothesized that inhibiting the TGF mechanism by administrating high dose furosemide would weaken synchronization among nearby NVUs.<br>
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In our second and third aim, we tested the effects of activating the TGF mechanism on synchronization among nearby NVUs, by administrating acetazolamide (n=6) and low dose furosemide (n=6) in male Lewis rats. We hypothesized that administrating acetazolamide and low dose furosemide enhance synchronization among nearby NVUs by activating TGF.<br>
In all the experiments, laser speckle contrast imaging (LSI), which can probe surface renal perfusion, was used to assess TGF phase coherence (PC), the number of edges with PC &gt; 0.6, the magnitude of decay of TGFPC and the initial and secondary decay associated with TGFPC. These parameters can be used to assess strength of synchronization among NVUs.<br>
Our results illustrate that high dose furosemide did not change PC and the number of edges with PC &gt; 0.6, indicating no changes in synchronization among nearby NVUs. Interestingly, high dose furosemide decreased the magnitude of decay of TGFPC showing stronger synchronization among NVUs. The inconsistency in these findings suggests the complexity of high dose furosemide as it causes vasodilation, increases macula densa solute delivery, changes TGF responsiveness and affects renin and ANG II levels. Moreover, technical issues could be another explanation for inconsistent findings as movements of the kidney surface due to pulse or/and respiration could be also captured by the LSI, which would affect the number of edges and PC.<br>
Additionally, acetazolamide and low dose furosemide increased mean PC, the number of edges with PC &gt; 0.6 and decreased the magnitude of decay of TGFPC, indicating stronger synchronization among nearby NVUs. It can be concluded from these findings that synchronization among NVUs can be enhanced by activating the TGF mechanism.</p>