PODOCYTE DAMAGE IS A CRITICAL STEP IN THE DEVELOPMENT OF GLOMERULOSCLEROSIS IN THE UNINEPHRECTOMIZED-DEOXYCORTICOSTERONE HYPERTENSIVE RAT

The progressive renal disease model of chronic inephrectomy-desoxycort icosterone-trimethylacetate (UNX-DOCA) hypertension is associated with mesangial proliferation as a major disease mechanism. A detailed stru ctural analysis of the alterations in glomerular structure which accom pany the development of sclerosis in this model has not been made. Mal e Munich-Wistar rats underwent UNX, received weekly injections of the aldosterone agonist DOCA and 1% sodium chloride as drinking solution a nd were compared with sham operated controls (CON). Thirty eight days after onset, UNX animals had an albuminuria of 183+/-180 mg/day versus 0.38+/-0.22 mg/day in CON. Kidneys were fixed by total body perfusion and renal tissue processed for light and electron-microscopy. Superfi cial and deep total glomerular volume increased from 2.18+/-0.15 (deep : 2.57+/-0.24) 10(6) mu m(3) in CON to 3.98+/-0.81 (deep: 3.95+/-0.63) 10(6) mu m(3) in UNX. In addition to overall tuft hypertrophy, struct ural analysis revealed severe destruction of tuft architecture with me sangial expansion and/or capillary ballooning, leading to local tuft e nlargements. Podocytes overlying the expanded areas appeared unable to adapt to cover the increased tuft surfaces. They developed severe les ions in cell architecture leading to denudation of glomerular basement membrane (GBM)-areas. ''Naked'' GBM appears to represent a nidus for hyalinosis, thrombosis and synechia formation, which progresses to seg mental sclerosis. In the UNX-DOCA model of chronic glomerular hyperten sion local mesangial expansion was frequently encountered but no evide nce was found that mesangial proliferation and matrix production proce eded to sclerosis. The crucial damage to the glomerulus in this model would appear to be attributable to podocyte failure, with the resultan t GBM denudation triggering synechia formation, hyalinosis and ultimat ely glomerulosclerosis.