Nephrotic syndrome causes selective damage to the glomerular charge or size barriers. Physiological mechanisms based onexperimental studies in the rat

Sammanfattning: Nephrotic syndrome causes selective damage to the glomerular charge or size barriers. Physiological mechanisms based on experimental studies in the rat. Department of Physiology, Institute for Physiology and Pharmacology, Göteborg University, Box 432, SE-405 30 Gothenburg, Sweden. Each day 180 liter of plasma is filtered across the glomerular capillaries of our kidneys. Less than 1 % of this fluid is excreted as urine with trace amounts of proteins. Still, the properties of the glomerular barrier are not completely understood and even less is known about the mechanisms of proteinuria. As a consequence there is no specific therapy for most renal disorders.This thesis focuses on the functional properties of the glomerular capillary wall in healthy and nephrotic rats. Our studies in isolated perfused kidneys reveal that the glomerular barrier indeed restricts macromolecules based on their size and charge, which is in qualitative agreement with the classical view. The charge selectivity is, however, considerably less pronounced than previously suggested and the functional pores are smaller. Moreover, elongated solutes with net negative charge had high fractional clearances in the entire glomerular filtration rate (GFR) range. Thus, an elongated solute shape can outweigh the effects of its net negative charge.We present a new theoretical model of the glomerular capillary wall with the charge and size barriers in series. According to the model there is a negatively charged gel with fixed negative charges (40-60 meq/L) that maintain lower concentrations of anionic molecules in the gel than in the plasma. Solutes will be further hindered to reach the urine by a size-selective membrane with numerous small and a few large pores, with radii of 45-50 and 75-115 Å, respectively. The glomerular filter is not a static membrane since increased GFR reduced the small pore radius and opened more large pores.Proteinuria was induced by puromycin aminonucleoside (PAN) or ischemia-reperfusion. PAN markedly reduced glomerular size selectivity; with increased small pore radius, more large pores, whereas the total pore area was decreased. However, PAN did not affect the charge density. The opposite was found for the ischemia-reperfusion, where the proteinuria could be explained by a reduced charge density, with no significant effects on glomerular size selectivity.Different components of the glomerular capillary wall seem to be responsible for the charge and size barriers. Thus, glomerular charge selectivity seems to be confined to the endothelial cell coat, whereas the size barrier more likely is situated in the slit membrane between the podocytes. This thesis has given us more information about the properties of the glomerular barrier in healthy and nephrotic rats. Our findings open new areas for further investigation that hopefully will improve the treatment for patients with renal disease.