Albumin Regulates the Na+/H+ Exchanger 3 in OKP Cells

Abstract

Abstract. Albumin filtered by the glomerulus is reabsorbed in the proximal tubule. We have shown previously that proteinuria stimulates the proximal tubular Na ϩ /H ϩ exchanger 3 (NHE3) in rats. Activation of NHE3 may be a pathophysiologically important factor in the development of renal salt and water retention observed in the nephrotic syndrome. For examining whether albumin is a specific inducer of proximal tubular Na ϩ /H ϩ exchange and to determine the molecular mechanisms by which it regulates Na ϩ /H ϩ exchange, the effect of albumin on NHE3 in opossum kidney cells was studied. Albumin activated Na ϩ /H ϩ exchange in a time-and dosedependent manner up to 100% in 48 h. In the early phase of stimulation (2 to 12 h), NHE3 activity was increased without changes in NHE3 protein and mRNA. At 24 h, increased NHE3 activity was accompanied by increase in cell surface NHE3 protein. The increase in surface NHE3 was associated with increased bidirectional trafficking of NHE3 protein between intracellular compartments and the cell surface. At 48 h, total cell NHE3 protein abundance and mRNA were increased as well. Whereas NHE3 translation was increased, NHE3 protein half-life remained unchanged. The effects of albumin on NHE3 protein abundance were modified by hydrocortisone in a complicated pattern. These results indicate that albumin directly regulates proximal tubular NHE3 at multiple levels.

Edema in the Nephrotic Syndrome

“…However the present in vitro studies on NHE3 was preceded by a recent study from the same group that demonstrated that the PAN model of nephrosis increases NHE3 in vivo (12). The current studies by Klisic et al (1) show that NHE3 is activated in vitro at several levels (functional activity, mRNA, trafficking) by albumin. There is a complicated interaction with hydrocortisone, which itself activates NHE3 at multiple levels.…”

“…Klisic et al (1) in this issue of JASN have added an interesting and important new finding to the complexity of our understanding of the nephrotic syndrome. They demonstrate that apical albumin directly stimulates NHE3 (sodium hydrogen exchanger 3), the major apical transporter responsible for proximal tubule sodium reabsorption.…”

Effects of receptor-mediated endocytosis and tubular protein composition on volume retention in experimental glomerulonephritis

“…In the search for potential sites of sodium retention along the renal tubule, the proximal tubule has been a focus (1,4,24,34,51). Protein overload may impair its structure, causing cytoskeletal changes, lipids may become accumulated, and inflammatory factors can be induced.…”

“…As a result, trafficking of transporters and channels may be impaired (22,32,40). Na ϩ /H ϩ exchanger 3 (NHE3)-dependent sodium reabsorption and lysosomal acidification may be affected (7,32,34), and coexpressed transport proteins such as aquaporin-1 (AQP1) and the Na ϩ -P i cotransporter IIa (NaPi-IIa) may be involved (22). Distally, regulation of the Na ϩ -K ϩ -2Cl Ϫ -cotransporter 2 (NKCC2) of thick ascending limbs (TAL) of Henle's loop may be affected as well (32), but the major distal site of retention has formerly been assigned to the collecting ducts (6,29), and recent work has been concentrated on the activation of the epithelial Na ϩ channel (ENaC) in a RAAS-independent way (3,33,38).…”

Na+/H+ Exchangers in Renal Regulation of Acid-Base Balance

“…Data in model systems of proximal tubule epithelia suggest possible mediation of albumin endocytosis and degradation by endosomal NHE3. [13][14][15] Intracellular [Na + ] in renal epithelia is less than 20 mmol/L, whereas basolateral [Na + ] ranges from 140 mmol/L in the cortex to as high as 300 mmol/L in the deep medulla. Basolateral NHEs undoubtedly will eject H + from the cell to the interstitium and hence are unlikely to contribute to luminal acidification.…”