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- Brown, Russell, 1966-
(author)
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The Influence of the Adenosine A1-receptor on Tubuloglomerular Feedback and Renin Release
- 2004
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Doctoral thesis (other academic/artistic)abstract
- The kidneys play a vital role in the maintenance of extracellular fluid and electrolyte balance and blood pressure. Adenosine, acting through the adenosine A1-receptor (A1R), and nitric oxide have been implicated in several of the regulatory mechanisms in the kidney. The A1R has been found to be present in the renal vasculature, primarily in the afferent arterioles, and in the proximal tubules. The tubuloglomerular feedback mechanism (TGF) is an important regulator of renal vascular tone and glomerular filtration rate. The aim of these investigations was to further elucidate the role of adenosine, acting through the A1R. Investigations on adenosine’s renal effects were performed on transgenic mice lacking the A1R.TGF response, elicited by increased distal salt load, was completely abolished in the A1R knockout (A1R -/- ) mice. Basal plasma-renin levels were found to be ~2-fold higher in the A1R -/- compared to the A1R wild-type (A1R+/+) mice. However, salt intake induced inverse changes in plasma-renin levels, indicating that adenosine tonically inhibits macula densa stimulated renin release. Anesthetized and conscious A1R -/- mice, measured telemetrically, had an increased blood pressure, which could be due to the increased plasma-renin levels. Despite the high plasma-renin levels, increased urinary sodium excretion was also observed in the A1R -/- animals. Ischemia caused a decrease in renal function in both A1R+/+ and A1R -/- mice. Ischemic preconditioning protected the A1R+/+ mice from subsequent ischemic episode but had no protective effect on the A1R -/- mice.Acute extracellular volume expansion greatly attenuates TGF sensitivity, thus facilitating the elimination of excess fluid. Acute inhibition of nNOS in volume-expanded rats was found to re-establish the attenuated TGF response caused by acute extracellular volume expansion.The results show that adenosine, acting through the A1R, plays an important role in mediating TGF response and consequently, regulating renin release, blood pressure, electrolyte balance and other vital renal mechanisms.
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- Rodrigo Blomqvist, Sandra, 1974, et al.
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Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1.
- 2004
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In: The Journal of clinical investigation. - 0021-9738. ; 113:11, s. 1560-70
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Journal article (peer-reviewed)abstract
- While macro- and microscopic kidney development appear to proceed normally in mice that lack Foxi1, electron microscopy reveals an altered ultrastructure of cells lining the distal nephron. Northern blot analyses, cRNA in situ hybridizations, and immunohistochemistry demonstrate a complete loss of expression of several anion transporters, proton pumps, and anion exchange proteins expressed by intercalated cells of the collecting ducts, many of which have been implicated in hereditary forms of distal renal tubular acidosis (dRTA). In Foxi1-null mutants the normal epithelium with its two major cell types - principal and intercalated cells - has been replaced by a single cell type positive for both principal and intercalated cell markers. To test the functional consequences of these alterations, Foxi1(-/-) mice were compared with WT littermates in their response to an acidic load. This revealed an inability to acidify the urine as well as a lowered systemic buffer capacity and overt acidosis in null mutants. Thus, Foxi1(-/-) mice seem to develop dRTA due to altered cellular composition of the distal nephron epithelium, thereby denying this epithelium the proper gene expression pattern needed for maintaining adequate acid-base homeostasis.
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