Mechanisms of Renal Injury Induced Chronic Hypertension

Li E. Yang, S. H. Ye, P. K.K. Leong, V.M. Campese, A. A. McDonough
Department of Physiology and Biophysics
University of Southern California, Keck School of Medicine
Los Angeles, CA 90089-9142

Introduction

There is a dynamic relationship between blood pressure (BP) and renal sodium reabsorption that determines the BP set point. Although it has been well recognized that regulation of sodium transport is critical for the maintenance of normal extracellular volume and BP, and that renal function is altered in hypertension, very little is understood about the molecular mechanisms of regulation of sodium transporters during a natriuretic response or in the generation or maintenance of hypertension. The sodium transport alteration may be either homeostatic compensations to elevated BP, or responsible for the generation and maintenance of hypertension:

Scenario 1
If BP is acutely increased by increasing peripheral resistance, proximal tubule (PT) sodium reabsorption will decrease to maintain tubuloglomerular feedback (TGF), and a natriuresis and diuresis will ensue to restore BP;

Scenario 2
I f renal sodium reabsorption is increased, BP will increase in order to match sodium excretion to sodium intake.

For scenario 1), the McDonough lab has investigated the molecular mechanisms responsible for the decrease
in PT sodium reabsorption and discovered that when BP is raised by constricting arterial beds for just 5 minutes, there is a retraction of the main PT sodium transporters including Na+/H+ exchanger (NHE3) from the apical brush border to intermicrovillar cleft and subapical endosomes, as well as a decrease in basolateral Na,K-ATPase activity. The redistribution of NHE3 was demonstrated with both subcellular fractionation strategy and with confocal microscopy.

For scenario 2), Campese and Ye developed a rat model of renal injury/neurogenic hypertension caused by an intrarenal injection of 50 µl 10% phenol. This small injury causes immediate and permanent çBP with increased sympathetic nervous system (SNS) activity. Renal denervation or nephrectomy of the injured kidney 3-4 weeks after the renal injury leads to normalization of BP.