We propose that a) the intrarenal tubuloglomerular feedback system (TGF) is critical to the regulation of the relation between tubular reabsorption and nephron filtration rate (SNGFR) and b) the mesangial cell contributes importantly by several mechanisms to the regulation of glomerular hemodynamics and ultrafiltration. Demonstration of the important regulatory contributions of TGF requires accurate methods to evaluate the sensitivity or slope around the turning point and the operating point (the normal late proximal tubular flow rate and SNGFR in unperturbed nephrons) and the half maximal SNGFR response (V1/2). Previous methods have relied upon evaluations using micropuncture tubular fluid collections while tubular flow rates are varied from the late proximal tubule. These methods generate very few data points around the operating point and data are discontinuous with very low time resolution due to the time required for collections. The sensitivity of TGF may have been underestimated by prior methods. Better high resolution methods of assessment are required to define these TGF parameters. We will utilize on-line methods to measure early proximal tubular flow rate, as an index of SNGFR, and late proximal flow rates using videometric methods to assess flow velocity and tubular diameter, in relation to the on-line evaluation of glomerular capillary hydrostatic pressure (Pg) and distal tubular C concentration using microelectrode in the same nephron units in both free flowing tubules and in the open loop mode. We propose that changes in TGF slope, operating point, open loop gain (OLG), and V1 2 are critical to renal regulatory responses to a) volume status, b) adaptations over time, & will c) define mechanisms of nephron:nephron TGF interaction, d) factors which influence the degree of nephron heterogeneity of TGF parameters and e) the role of the renin-angiotensin system, eicosanoids and EDRF or nitric oxide in TGF regulatory processes. We will also utilize antibodies to thymocyte-1 antigen on mesangial cells to produce mesangial cell lysis (1 day) to verify and examine the concept that the mesangial cell is critical to a) TGF, b) glomerular hemodynamic responses to volume status, c) autoregulation and d) response to hormonal agonists. Utilizing these studies a deductive process will permit conclusions as to the role of the mesangial cell in regulation of afferent and efferent arteriolar resistances, the ultrafiltration coefficient and transduction of TGF signals to the effector. TGF contributions to a variety of physiologic and pathophysiologic conditions, i.e. 1) renal functional reserve, 2) tubular injury and 3) reductions in renal mass will be specifically examined using these newer techniques. Newer on-line methods in relatively undisturbed nephrons are superior to previous approaches because of the greater data generated and the continuous nature of these data and will permit detailed evaluation of the dynamic role and regulation of TGF and the function of the glomerular mesangial cell.
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