Angiotension II (Ang II) is a major hormone involved in regulating glomerular function. It has specific high affinity receptor sites located primarily on mesangial cells, through which it initiates contraction, decrease in capillary surface area and ultrafiltration coefficient. Ang II binding to isolated glomeruli is influenced by changes in sodium balance, exposure to Ang II in vivo and other hormonal manipulations. However, the extent to which such receptor changes modulate cellular responses and ultimately glomerular and mesangial cell function has not been determined.
The aim of these studies is to link binding to Ca++ transport, glomerular contractility and prostaglandin (PG) and/or thromboxane synthesis. The ultimate aim is to determine temporal patterns as well as qualitative and quantitative relationships linking binding and responses. Kd and receptor density will be correlated with the ED50 for contraction and maximum contractile response of whole glomeruli and cultured mesangial cells. Dose response relationships Ang II's effect on PG and thromboxane synthesis will be determined using RIA for both whole glomeruli and cultured mesangial cells. Similarly, dose response relationships of Ang II-induced effects on Ca++ pool size and rate of influx of efflux will be constructed for both isolated glomeruli and cultured mesangial cells using 45Ca++ and/or Quin-2. Ang II receptors and responses of isolated rat glomeruli will be assessed following Ang II infusion, aldosterone, dexametharone, and estrogen treatment, alterations in potassium balance and the two kidney one clipped Goldblatt hypertension model. The extent of regulation of receptors and responses by peptides, steriods and electrolytes will be assessed with cultured mesangial cells. The vasoactive component of arginine vasopressin (AVP) shares numerous properties with Ang II as to mechanism of action on the glomerulus in vivo and cultured mesangial cell. AVP is released in vivo by Ang II, mineralocorticoid, and low K+ diet all of which affect Ang II receptors yet its ultimate role in physiology is poorly understood. We have also recently demonstrated that AVP stimulates PG release from isolated rat glomeruli making feasible linking of binding, contraction, and PG biosynthesis using isolated glomeruli. Therefore, AVP receptors and responses will be studied in parallel with Ang II using both cellular preparations.
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