Dahl salt-sensitive (Dahl S) hypertensive rats are more susceptible to glomerular injury compared with other genetically hypertensive models such as spontaneously hypertensive rats and Milan hypertensive rats. The mechanism for the greater susceptibility to glomerular injury in Dahl S rats remains unknown. The purpose of the proposed studies is to determine the role of the resetting of the tubuloglomerular feedback (TGF) mechanism in increasing the susceptibility to glomerular injury in Dahl S rats and the contribution of altered adenosine metabolism in the kidney to the resetting of TGF mechanisms and glomerular hypertension in these rats. They will determine the mechanism resulting in an abnormality of adenosine metabolism in the kidney in Dahl S/Jr rats using biochemical techniques such as HPLC, enzyme kinetic assay and Western blot. They will localize 5'-nucleotidase and adenosine deaminase in microdissected glomeruli and tubules and identify the segments in the nephron responsible for altered renal adenosine metabolism in Dahl S/Jr rats using isoelectric focussing and gel electrophoresis techniques. They will determine the contribution of alteration in renal adenosine metabolism to the abnormality of glomerular dynamics in Dahl S/Jr rats using micropuncture technique. They will also determine the role of altered renal adenosine metabolism in the resetting of the TGF response in Dahl S/Jr rats. Finally, they will determine the mechanism by which chronic administration of dipyridamole increases renal adenosine levels and the role of increased renal adenosine in the restoration of the TGF response and the prevention of the rapid progression of glomerular injury in Dahl S/Jr rats. These studies will confirm that an abnormality of renal adenosine metabolism contributes to the rapid progression of glomerular injury in Dahl S/Jr rats by resetting TGF mechanism and increase in endogenous adenosine associated with dipyridamole treatment not only prevents hypertension, but also protects the kidney from hypertensive glomerular injury in Dahl S/Jr rat exposed to high salt diet.
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