Abstract 134: Proximal Tubule-mediated Control of Albumin Balance During the Development of Salt-sensitive Hypertension

Abstract

Salt-induced hypertension and the associated renal and cardiovascular complications affect a large population and are one of the leading causes of CKD. It is widely accepted that albuminuria is a strong predictor of kidney injury and cardiovascular outcome. Despite the indisputable significance of albuminuria as one of the most important factors for predicting morbidity and mortality in patients with cardiovascular diseases, the events leading to the excessive filtration of albumin into the urine are not well understood. The goal of the current study was to determine the mechanisms contributing to albuminuria in the kidney of the Dahl salt-sensitive (SS) rat, a widely used model of salt-induced hypertension. The SS rats when fed a high salt (HS) diet develop progressive elevations in urinary albumin and mean arterial blood pressure (MAP). Intravital imaging analyses of the kidneys indicate increased loading of proximal tubules (PT) with filtered albumin at the early stage of the development of hypertension. Further progression of the disease strongly correlated with significant PT damage as indicated by the impaired albumin reabsorption, increased prevalence of granular casts, and necrosis of PT epithelial cells. To prevent PT albumin overload and further development of kidney damage PT reabsorption blocker L-Lysine (17 mg/ml) was added to the drinking water offered ad libitum, and the measurements of MAP repeated continuously on HS. Treatment of SS rats with L-lysine significantly reduced the progression of salt-induced hypertension (165±4 vs 133±2 mmHg at 14D on HS, control vs L-Lysine). L-lysine significantly attenuated the development of progressively increased albuminuria and restored serum albumin balance in hypertensive animals (1.5±0.25 vs 13.28±2.14 and 6.91±1.07 24 hrs Alb/Cre; 2.98±0.07 vs 2.46±0.08 and 2.86±0.05 g/dL of serum Alb at low salt vs 14D on HS, control, and L-Lysine treated, respectively). We conclude that salt-induced increase of albumin load at the PT results in loss of albumin reuptake, reduction of albumin serum concentrations and progression of albuminuria in SS hypertensive rats. The protection of PT against extensive albumin load can significantly reduce renal damage and development of high blood pressure.