Heart failure (HF) is associated with a reduced effective circulating volume that drives sodium and water retention and extracellular volume expansion. We therefore hypothesized that Na(+)/H(+) exchanger isoform 3 (NHE3), the major apical transcellular pathway for sodium reabsorption in the proximal tubule, is upregulated in an experimental model of HF. HF was induced in male rats by left ventricle radiofrequency ablation. Sham-operated rats (sham) were used as controls. At 6 wk after surgery, HF rats exhibited cardiac dysfunction with a dramatic increase in left ventricular end-diastolic pressure. By means of stationary in vivo microperfusion and pH-dependent sodium uptake, we demonstrated that NHE3 transport activity was significantly higher in the proximal tubule of HF compared with sham rats. Increased NHE3 activity was paralleled by increased renal cortical NHE3 expression at both protein and mRNA levels. In addition, the baseline PKA-dependent NHE3 phosphorylation at serine 552 was reduced in renal cortical membranes of rats with HF. Collectively, these results suggest that NHE3 is upregulated in the proximal tubule of HF rats by transcriptional, translational, and posttranslational mechanisms. Enhanced NHE3-mediated sodium reabsorption in the proximal tubule may contribute to extracellular volume expansion and edema, the hallmark feature of HF. Moreover, our study emphasizes the importance of undertaking a cardiorenal approach to contain progression of cardiac disease.

Cumulative epidemiological evidence indicates that the presence of microalbuminuria predicts a higher frequency of cardiovascular events, peripheral disease, and mortality in essential hypertension. Microalbuminuria may arise from increased glomerular permeability and/or reduced proximal tubular reabsorption of albumin by receptor-mediated endocytosis. This study aimed to evaluate the temporal pattern of urinary protein excretion and to test the hypothesis that progression of microalbuminuria is associated with decreased protein expression of critical components of the endocytic apparatus in the renal proximal tubule of spontaneously hypertensive rats (SHR). We found that urinary albumin excretion increased progressively with blood pressure in SHR from 6 to 21 wk of age. In addition, SDS-PAGE analysis of urinary proteins showed that microalbuminuric SHR virtually excreted proteins of the size of albumin or smaller (<70 kDa), typical of tubular proteinuria. Moreover, the protein abundance of the endocytic receptors megalin and cubilin as well as of the chloride channel ClC-5 progressively decreased in the renal cortex of SHR from 6 to 21 wk of age. Expression of the vacuolar H⁺-ATPase B2 subunit was also reduced in the renal cortex of 21-wk-old compared with both 6- and 14-wk-old SHR. Collectively, our study suggests that enhanced urinary protein excretion, especially of albumin, may be due, at least in part, to lower expression of key components of the apical endocytic apparatus in the renal proximal tubule. Finally, one may speculate that dysfunction of the apical endocytic pathway in the renal proximal tubule may contribute to the development of microalbuminuria in essential hypertension.

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.Support: FAPESP

No abstract

No abstract