Progression of microalbuminuria in SHR is associated with diminished expression of proteins that belong to the receptor-mediated endocytosis macromolecular complex

Abstract

Microalbuminuria is recognized to be a risk factor for cardiovascular and kidney disease and is associated with morbidity and mortality in hypertensive patients. It arises as a consequence of increased glomerular permeability and/or reduced tubular reabsorption. The aims of the present study were: (1) to analyze the temporal evolution and the pattern of urinary protein excretion in spontaneously hypertensive rats (SHR), and (2) to evaluate whether the expression of proteins implicated in receptor-mediated endocytosis in the renal proximal tubule of SHR can vary with blood pressure. Urinary protein excretion was evaluated in 6, 14 and 21 week-old SHR and in Wistar rats of corresponding age. Daily urinary protein excretion increased with the development of hypertension in SHR (15 ± 1; 71 ± 2 and 112 ± 6 mg/day at 6, 14 and 21 weeks respectively), but remained unchanged in normotensive rats. SDS-PAGE analysis of urinary proteins showed that SHR displayed a progressive increase of intact urinary albumin excretion with age. Progression of microalbuminuria highly correlated with elevation of arterial blood pressure in SHR (0.91; P<0.0001). Moreover, during the period of 6 to 21 weeks of age, SHR only excreted proteins of the size of albumin or smaller. The expression of the endocytic receptors megalin and cubilin, the B2-subunit of the H+-ATPase and the ClC-5 chloride channel decreased as blood pressure increased in SHR but remained unaltered in Wistar rats. Furthermore, western blot analysis of urine samples revealed that the urinary excretion of transferrin, a protein known to be reabsorbed via receptor mediated endocytosis, increases as blood pressure increases in SHR. Taken together these data suggest that SHR displays tubular proteinuria after development of hypertension at least in part due to a decrease of some components of the receptor-mediated endocytosis macromolecular complex.