Pathologic Glomerular Responses to Vasoactive Substances

Richardson, Walter

Abstract

Progressive glomerulosclerosis is present in kidneys approaching end stage in many diseases and may represent a final common pathway of nonimmunologic renal injury. It is seen in such diverse conditions as diabetes mellitus, reflux nephropathy, idiopathic focal glomerulosclerosis and hypertensive nephrosclerosis. This project is intended to test the hypothesis that progressive glomerular sclerosis seen in noninflammatory conditions where hyperfiltration or hyperperfusion occur results from three mechanisms; excessive contraction of mesangial cells occluding capillaries, excessive mesangial expansion occluding capillaries, or an imbalance of arteriolar contraction causing excessive capillary pressure, dilatation and thrombosis. This will be done using morphometric methods to evaluate the contraction of renal glomerular afferent and efferent arterioles, capillaries and mesangium to vasoactive substances in normal, partially nephrectomized and hypertensive rats. Kidney tissue will be processed three ways: a. Perfused, per aorta, in situ, with the test vasoactive substance, then perfusion fixed and examined by transmission electron microscopy (TEM). b. Perfused as above but after fixation perfused with plastic. The plastic casts will be examined by scanning electron microscopy (SEM). c. Isolated glomeruli will be incubated with vasoactive substances in vitro, then fixed and examined by TEM. Glomerular afferent and efferent arteriolar and glomerular capillary lumen diameters as well as glomerular capillary tuft diameter will be measured on SEM photographs. Glomerular basement membrane cross sectional length, capillary lumen and mesangial cross sectional areas will be measured on TEM photographs. From these measurements arteriolar contractile responses, folding or wrinkling of the basement membrane and relative capillary lumen and mesangial areas will be calculated. Examining these changes in disease states which lead to progressive glomerulosclerosis is an important step to altering the chronic loss of renal function seen in clinical states where glomeruli are subjected to high perfusion rates or high perfusion pressures.