Elucidation of Tubulo-Glomerular Feedback Mechanisms

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It is speculated that an abnormal tubulo-glomerular feedback (TGF) activity may induce the nephropathy via renal hemodynamic changes. However, there are no useful technique to evaluate the TGF activity. The purposes of this project are to develop the in vivo dynamic method to evaluate TGF activity, to evaluate the TGF activity in renal disease models, and to determine a possible mediator in TGF mechanisms.1.Development of in vivo dynamic method to evaluate TGF activity : We introduced the intravital CCD-video microscopy that allowed direct in vivo visualization of the renal microcirculation, and measured both afferent and efferent arteriolar diameters in rats. In Sprague-Dawley (SD) rats, the basal afferent and efferent arteriolar diameters were 8.57+/-0.43 and 7.31+1-0.81 um, respectively. Acetazolamide significantly decreased the afferent arteriolar diameter (AAD) to 6.64+/-0.57 um, but did not affect the efferent arteriolar diameter. Furosemide reversed the acetazolamide-induced aff … More erent constriction.2. TGF activity in Dahl salt sensitive (DS) rats : DS rats were given high salt diet (H : 8% NaCl) and low salt diet (L : 0.3% NaCl). Basal AADs were similar between SD and DS/L rats (8.57+/-0.43 and 8.74+/-0.20 um). In DS/L rats, acetazolamide induced the afferent constriction and furosemide reversed the acetazolamide-induced afferent constriction. In contrast to SD or DS/L rats, DS/H rats showed smaller basal AAD (6.09+/-0.49 um). Acetazolamide failed to reduce AAD, but furosemide restored AAD to that in DS/L rat. Thus, it can be considered that TGF mechanisms might be activated in DS/H rats.3. Determination of mediators in TGF mechanisms : The renal interstitial concentration of adenosine, ATP and NO metabolites. We observed the positive correlation between TGF-mediated changes in renal vascular resistance and renal interstitial concentration of ATP.Thus, we could develop the in vivo dynamic method to evaluate TGF activity and show the abnormal TGF activity in DS/H rats. In addition, we could pick up ATP as a mediator in TGF mechanism. Based on these findings we believe to be able to develop the new strategy for the treatment of nephropathy. Less