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      Effect of Endothelin 1 on Proximal Reabsorption and Tubuloglomerular Feedback

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          Endothelin 1 (ET–1) is a powerful constrictor of the afferent glomerular artery, implicated in the occurrence of both functional and acute renal failure. Besides being produced by the endothelium, ET–1 is also secreted by proximal tubular cells, suggesting that it may act as an endoluminal messenger. The present study is intended to verify whether ET–1 may play a role in the tubuloglomerular feedback system. The experiments were performed in rat superficial glomeruli. In 25 nephrons we measured by the total collection technique the single–nephron glomerular filtration rate (SNGFR; nl/min) and reabsorption rates before (control) and during microinjection (MIJ) of ET–1 10<sup>–7</sup> M into the first proximal convolution or Bowman’s space. The SNGFR rose from 27±3 to 61±11 nl/min (p<0.01), the percent proximal reabsorption rose from 43 to 74%, and the absolute reabsorption rose from 13±2 to 46±11 nl/min (p<0.01). In additional 23 nephrons the collections were performed at the earliest distal convolution accessible on the renal surface, while MIJ was performed in the last proximal convolution of the same nephrons. The SNGFR rose during MIJ from 22±3 to 40±6 nl/min (p<0.01), the percent reabsorption rose from 61 to 66% (p>0.77), and the absolute reabsorption rose from 12±2 to 26±4 nl/min, (p<0.003). Exposure of the macula densa to intraluminally injected ET–1 causes an abrupt increase in SNGFR of the experimental nephron, in the absence of changes in systemic and renal hemodynamics. During proximal MIJ, ET–1 may have reached the macula densa during the time preceding the beginning of collection and interruption of the delivery of fluid to the distal nephron. ET–1 directly stimulates fractional and absolute volume reabsorption along the proximal tubule. Proximal secretion and/or filtration of ET–1 could represent a physiological mechanism to activate the tubuloglomerular feedback, eliciting a response opposite to that triggered by systemic and intrarenal infusion.

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          Most cited references 5

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          Endothelin release by rabbit proximal tubule cells: modulatory effects of cyclosporine A, tacrolimus, HGF and EGF.

           P Jehle,  A Gruenert,  C Grill (1998)
          Previous studies have suggested that endothelins, a family of 21 amino acid peptides with potent vasoconstrictive and mitogenic properties, are involved in the pathogenesis of acute and chronic renal failure. In addition, endothelin seems to play an important role in mediating the nephrotoxic side effects of cyclosporine A (CsA) and tacrolimus. The present study investigated the production of endothelin-1 (ET-1) and endothelin-3 (ET-3) by bipolar differentiated rabbit proximal tubule cells (PT-1 cells), and the modulatory effect of CsA, tacrolimus, hepatocyte growth factor (HGF) and epidermal growth factor (EGF) on ET-1 and ET-3 release. ET-1 and ET-3 mRNA was detected by RT-PCR, immunoreactive endothelin was localized to PT-1 cells by immunofluorescence staining with antibodies against ET-1 and ET-3. ET-1 and ET-3 release into the culture medium was determined by specific radioimmunoassays after solid phase extraction. PT-1 cells exhibited a time-dependent increase of ET-1 release up to an incubation period of 36 hours, whereas ET-3 release already reached a steady state level after four hours. PT-1 cells, cultured on filter membranes, released a significantly higher amount of immunoreactive ET-1 into the basolateral compartment than into the apical compartment. ET-3 release did not differ significantly between the basolateral and the apical compartment. Supplementation of the cell culture medium with 10% fetal calf serum induced a marked increase of the basolateral and apical ET-1 release, whereas ET-3 release was only slightly increased. CsA and tacrolimus (0.5 to 5000 microgram/liter) induced a significant, dose-dependent increase of ET-1 and ET-3 release by PT-1 cells with a maximum stimulation at a CsA concentration of 500 microgram/liter (P < 0.001) and a tacrolimus concentration of 50 microgram/liter (P < 0.001). HGF and EGF (10-10 to 10-8 mol/liter) exerted a significant (P < 0.001) dose-dependent inhibitory effect on ET-1 release, whereas ET-3 release was not significantly reduced. Coincubation of PT-1 cells with CsA or tacrolimus and HGF or EGF also resulted in a marked reduction of ET-1 release. The present data suggest that ET-1 and ET-3 release by cultured rabbit proximal tubule cells are regulated differently, and that the stimulatory effect of CsA and tacrolimus on ET-1 release is antagonized by HGF and EGF.
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            Adenosine as a possible mediator of metabolic control of glomerular filtration rate

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              Contribution of endothelin receptors in renal microvessels in acute cyclosporine-mediated vasoconstriction in rats


                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                02 November 2000
                : 23
                : 6
                : 360-365
                Department of Internal Medicine and DPMSC, University of Udine, Medical School, Udine, Italy
                25984 Kidney Blood Press Res 2000;23:360–365
                © 2000 S. Karger AG, Basel

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                Tables: 2, References: 33, Pages: 6
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