Renine is an enzyme which is synthesized and released from specialized cells in the wall of the afferent arteriole at the juxtaglomerular apparatus. Release of renin appears to be the major controlling step in generation of the potent vasoconstrictor and aldosterone secretagogue angiotensin II. There is evidence that abnormalities in control of renin secretion may play a role in certain forms of hypertension and perhaps in other disease states. Arterial pressure and tubular fluid composition at the adjacent macula densa are generally believed to be the two major physiological variables which control the rate of renin secretion. The present investigation aims to clarify the cellular mechanisms for these control processes. Proposed studies utilize a newly developed approach which applies isolated perfused tubule methods to the microdissected juxtaglomerular apparatus. With this method, the tubule segment containing the macula densa can be perfused, fluid composition at the macula densa manipulated, and the response of single JGA renin secretion measured. We propose to use this technique to determine the role of prostaglandins, adenosine, and local intertitial osmolarity in the macula densa mechanism for control of renin secretion. In other studies, the afferent arteriole is cannulated and arteriolar stretch varied, permitting study of the mechanisms underlying the pressure sensitivity of renin release. We plan to evaluate the role of stretch-dependent activation of calcium channels and the endothelium in pressure-sensitive renin release. These new in vitro methods offer substantial advantage over classic methods for study of the baroreceptor and macula densa mechanisms. Agonist and antagonist studies are facilitated by direct access to tubular, intravascular and interstitial compartments. Direct visualization and access to individual cells permit use of optical and electrophysiological methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK040042-01
Application #
3240120
Study Section
General Medicine B Study Section (GMB)
Project Start
1988-04-01
Project End
1993-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Yang, T; Huang, Y; Heasley, L E et al. (2000) MAPK mediation of hypertonicity-stimulated cyclooxygenase-2 expression in renal medullary collecting duct cells. J Biol Chem 275:23281-6
Arend, L J; Smart, A M; Briggs, J P (2000) Mouse beta(6) integrin sequence, pattern of expression, and role in kidney development. J Am Soc Nephrol 11:2297-305
Yang, T; Park, J M; Arend, L et al. (2000) Low chloride stimulation of prostaglandin E2 release and cyclooxygenase-2 expression in a mouse macula densa cell line. J Biol Chem 275:37922-9
Schnermann, J; Traynor, T; Pohl, H et al. (2000) Vasoconstrictor responses in thromboxane receptor knockout mice: tubuloglomerular feedback and ureteral obstruction. Acta Physiol Scand 168:201-7
Yang, T; Sun, D; Huang, Y G et al. (1999) Differential regulation of COX-2 expression in the kidney by lipopolysaccharide: role of CD14. Am J Physiol 277:F10-6
Traynor, T R; Schnermann, J (1999) Renin-angiotensin system dependence of renal hemodynamics in mice. J Am Soc Nephrol 10 Suppl 11:S184-8
Traynor, T; Yang, T; Huang, Y G et al. (1999) Tubuloglomerular feedback in ACE-deficient mice. Am J Physiol 276:F751-7
Traynor, T R; Smart, A; Briggs, J P et al. (1999) Inhibition of macula densa-stimulated renin secretion by pharmacological blockade of cyclooxygenase-2. Am J Physiol 277:F706-10
Yang, T; Michele, D E; Park, J et al. (1999) Expression of peroxisomal proliferator-activated receptors and retinoid X receptors in the kidney. Am J Physiol 277:F966-73
Yang, T; Schnermann, J B; Briggs, J P (1999) Regulation of cyclooxygenase-2 expression in renal medulla by tonicity in vivo and in vitro. Am J Physiol 277:F1-9

Showing the most recent 10 out of 41 publications