It is generally accepted that albuminuria is a molecular marker of renal injury and plays a significant role in the development of hypertension, congestive heart failure, metabolic syndrome, and chronic kidney disease. While increased albumin excretion has been shown to be a strong predictor of cardiorenal disorders, a paucity of knowledge exists regarding the initiating events. The goal of the current study is to determine the contribution of the renal oxidative stress, glomeruli and proximal tubules to albuminuria in the kidney of a rat model of salt-sensitive hypertension, the Dahl SS rat. To uncover these mechanisms, we will apply the novel intravital two-photon imaging to investigate changes in renal function that occur prior to and during the development of salt-sensitive hypertension. This in vivo method facilitates a high-powered and time-dependent view on the glomerular filtration barrier, microvascular blood flow, assessment of glomerular and peritubular vasculature permeability and proximal tubule function, unique characteristics that are not achieved by any other technique. To evaluate mechanisms of oxidative stress in vivo we will use novel biosensor approach to monitor changes of interstitial H2O2 concentrations in the kidney. Moreover, our pilot experiments revealed that reduction of albumin reuptake and oxidative stress in proximal tubule by administration of L-lysine prevents proximal tubule damage.The Specific aims are: 1) to define the changes in both glomerular hydrodynamics and permeability to albumin in SS rats fed a high salt diet; 2) to identify the contribution of proximal tubule reuptake and transcytosis of albumin during the development of hypertension and albuminuria; 3) to define the mechanisms of proximal tubule damage during the development of albuminuria and prevent increase of blood pressure by the pharmacological control of albumin reuptake in proximal tubule.
|Program type||Scientist Development Grant|
|Effective start/end date||07/01/2017 → 06/30/2020|