Glomerular ultrafiltration coefficient, Kf or LpA, is one determinant of glomerular filtration rate. The long term goal of the proposed investigations is to gain understanding of the humoral, metabolic and anatomic mechanisms responsible for controlling Kf. Kf is modulated during altered physiologic states and by the action of humoral mediators. Specifically, Kf is diminished during volume depletion and during infusion of angiotensin II and other vasoactive hormones and may be increased during volume expansion and following infusion of atrial natriuretic peptide. These variations in Kf persist in vitro in non-perfused glomeruli and thus cannot result solely from dynamic changes in filtration area secondary to mesangial cell contraction. Rather, they are most consistent with modulation of capillary hydraulic conductivity, Lp. The proposed studies address the mechanisms responsible for modulation of Kf and Lp as they are observed in the absence of perfusion. Established methods for studying filtration by isolated glomeruli using videomicroscopy will be used. Changes in capillary volume during filtration will be confirmed using differential interference contrast microscopy. The effects of mesangial contraction on glomerular volume and on capillary configuration and area will also be assessed using video, radioisotope and morphometric techniques. Detailed morphometric examination of the paracellular pathway for filtration on the epithelial aspect of the Hypotheses to be tested are: 1. Mesangial contraction changes capillary configuration and does not affect capillary surface area. Mesangial tone is altered by responses to several hormones but varies independently from Lp. 2. Glomerular epithelial cells control Lp. Lp is modulated by humoral responses and increases when intracellular levels of cAMP increase and decreases when levels of cGMP increase. 3. Lp is modulated by changes in the filtration pathway that result from changes in epithelial foot processes and the filtration slit-pore. These changes include retraction or extension of the foot processes and changes in the width of the intercellular pathway immediately adjacent to the basement membrane. The results of these studies will enable us to determine whether modulation of Kf and Lp is a direct correlate of mesangial contraction or whether, as we propose, Lp varies with epithelial cell cyclic nucleotides and is independent of mesangial tone.
