Hypertonicity-induced Aquaporin-1 (AQP1) Expression Is Mediated by the Activation of MAPK Pathways and Hypertonicity-responsive Element in the AQP1 Gene

Abstract

Aquaporin-1 (AQP1) is a water channel that is induced by hypertonicity. The present study was undertaken to clarify the osmoregulation mechanism of AQP1 in renal medullary cells. In cultured mouse medullary (mIMCD-3) cells, AQP1 expression was significantly induced by hypertonic treatment with impermeable solutes, whereas urea had no effect on AQP1 expression. This result indicates the requirement of a hypertonic gradient. Hypertonicity activated ERK, p38 kinase, and JNK in mIMCD-3 cells. Furthermore, all three MAPKs were phosphorylated by the upstream activation of MEK1/2, MKK3/6, and MKK4, respectively. The treatments with MEK inhibitor U0126, p38 kinase inhibitor SB203580, and JNK inhibitor SP600125 significantly attenuated hypertonicity-induced AQP1 expression in mIMCD-3 cells. In addition, hypertonicity-induced AQP1 expression was significantly reduced by both the dominant-negative mutants of JNK1-and JNK2-expressing mIMCD-3 cells. NaCl-inducible activity of AQP1 promoter, which contains a hypertonicity response element, was attenuated in the presence of U0126, SB203580, and SP600125 in a dose-dependent manner and was also significantly reduced by the dominantnegative mutants of JNK1 and JNK2. These data demonstrate that the activation of ERK, p38 kinase, and JNK pathways and the hypertonicity response element in the AQP1 promoter are involved in hypertonicity-induced AQP1 expression in mIMCD-3 cells.Aquaporins (AQPs), 1 a family of water channels, function as a water-selective transporting protein in cell membranes (1). Aquaporin-1 (AQP1) was first discovered in human erythrocytes as a water channel for high osmotic water permeability (2, 3). In addition to erythrocytes, AQP1 is abundantly present in the epithelium of kidney proximal tubules and descending thin limbs and endothelium of the descending vasa recta (4). AQP1 has been suggested to be important in constitutive water reabsorption, especially in the epithelial cells of the renal medulla.The AQP1-expressing vasa recta of the renal medulla are critical in generating and maintaining an axial osmotic gradient through the medulla (5). Sodium chloride (NaCl), urea, and water transporters in the inner medullary collecting duct (IMCD) all play an important role in the regulation of solutefree water excretion in the kidney. Although most cells in mammals are not normally stressed by hypertonicity, epithelial cells of the renal medulla are constantly subjected to a hypertonic condition. Specifically, as a consequence of the urinary concentrating mechanism, cells in the renal inner medulla are normally exposed to a variety of high concentrations of NaCl and urea. Hypertonicity, which results from a high concentration of salt and urea, provides a mechanical stress to shrink medullary cells. However, medullary cells adapt to hypertonicity by a variety of responses through an acute influx of NaCl and water (6), chronic accumulation of organic osmolytes (7), and acute activation of immediate early and heat shock genes (8, 9). Although the amounts of total RNA tr...

Acute Hypertonicity Alters Aquaporin-2 Trafficking and Induces a MAPK-dependent Accumulation at the Plasma Membrane of Renal Epithelial Cells

“…Similar to results of the present study, p38, ERK1/2, and JNK MAPK activation by hypertonicity has been demonstrated in inner medullary collecting duct cells and in cells of the medullary thick ascending limb of Henle's loop (43)(44)(45). A role of p38, ERK and JNK in the transcriptional regulation of various aquaporins by hypertonicity has been shown in renal and lung epithelial cells and in astrocytes (45)(46)(47). Data from our present study indicate that MAPKs additionally participate in the accumulation of AQP2 at the plasma membrane, but not at the TGN, in renal CD principal cells immediately following hypertonic challenge.…”

Water transport across the peritoneal membrane

“…AQP1 is the most abundant isoform in the peritoneum, and the only one that has been consistently located in the capillary endothelium. It must be noted that the expression of AQP1 in mesothelial, endothelial and epithelial cells may be induced by exposure to osmotic agents in vitro, reflecting the presence of hypertonicity response elements in the promoter (27,28). Because the mesothelium does not represent a significant functional barrier for water transport in PD, the functional importance of water channels at that level remains unclear.…”

Role of proneuregulin 1 cleavage and human epidermal growth factor receptor activation in hypertonic aquaporin induction

“…In addition to up-regulation of organic osmolyte transporters, hypertonicity induces expression of aquaporin (AQP) waterchannel proteins (15)(16)(17). Aquaporins are the primary determinants of osmotic gradient-dependent rapid water movement in or out of cells (18).…”

“…Aquaporins are the primary determinants of osmotic gradient-dependent rapid water movement in or out of cells (18). Hypertonic induction of AQP5, a waterchannel protein expressed in lung and several secretory epithelia (16), and AQP1, which is expressed at multiple sites including lung and kidney (16,17), require activation of mitogen-activated protein kinase (MAPK) signaling cascades, which are known to participate in osmotic signaling in yeast and mammals (19). MAPK activation often follows the activation of G proteincoupled receptors (GPCRs) and͞or receptor tyrosine kinases (RTKs), e.g., the epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor (HER).…”