Distinct cellular pathways for resistance to urea stress and hypertonic stress

Abstract

Lee SD, Choi SY, Kwon HM. Distinct cellular pathways for resistance to urea stress and hypertonic stress. Am J Physiol Cell Physiol 300: C692-C696, 2011. First published December 22, 2010; doi:10.1152/ajpcell.00150.2010.-During antidiuresis with elevated vasopressin, urea accumulates in the renal medulla to very high concentrations, imposing considerable cellular stress. How local cells cope with urea stress is relevant to the whole kidney because the renal medulla is the major site of residence for the renal stem cells. Previous studies showed that renal cells were incapable of preconditioning in moderate urea concentrations to enhance resistance to urea stress. Instead, preconditioning in moderately high salinity (moderate hypertonicity) has been shown to promote resistance to urea stress due to the induction of the molecular chaperone heat shock protein 70 (Hsp70), which is mediated by the transcription factor tonicityresponsive enhancer binding protein (TonEBP). Here we report that cell lines derived from the kidney and fibroblasts display enhanced resistance to urea stress after pretreatment in moderate, nonstressful concentrations of urea. Using TonEBP knockdown and immunoblot analyses, we demonstrate that TonEBP and Hsp70 are dispensable for the increased resistance to urea stress. These data suggest that cells in the renal medulla are capable of overcoming urea stress by activating distinct cellular pathways. tonicity-responsive enhancer binding protein; heat shock protein 70; hypertonicity; renal medulla OSMOLALITY IN THE RENAL MEDULLA is high due to the operation of urinary concentrating mechanism. The cortex is isotonic but the osmolality gradually increases along the cortico-medullary axis starting from the outer medulla down to the tip of the papilla, where tissue osmolality reaches over 2,500 mosmol/ kgH 2 O in rodents during antidiuresis with elevated vasopressin (see Ref. 1 for a review). Urea and salt, two principal solutes in the renal medulla, differ in their osmotic action. Salt distributes mainly in the interstitium, i.e., excluded from the cell, and imposes hypertonic stress to the cell. While urea is an effective osmotic agent driving water reabsorption in the collecting duct, it is generally not excluded from the cell due to high membrane permeability.Despite the differences in their osmotic action, both hyperosmotic salt (hypertonicity) and urea impose cellular stress as they kill renal cells in culture in a dose-dependent manner (8,14). Underlying cellular mechanisms involved in the stress appear distinct for the two solutes since urea-induced cell death is not associated with reduced RNA and protein synthesis like hypertonicity-induced cell death (14). On the other hand, cells in the renal medulla in situ cope with the hyperosmolality without signs of distress as cell death is not detectable even during severe antidiuresis (15,19). Kidney-derived cells in culture can be preconditioned to enhance resistance to hyperAddressfor reprint requests and other correspondence: H. Moo Kwon, 655 ...

Osmotic Stress–Induced Defective Glial Proteostasis Contributes to Brain Demyelination after Hyponatremia Treatment

“…The cellular response to hypertonic stress caused by urea is notably different from hypertonic saline, 32 and correction of chronic hyponatremia with urea can alleviate neuropathologic manifestations of ODS. [33][34][35] Therefore, we wanted to investigate the effect of correction of hyponatremia with urea as opposed to hypertonic saline with regards to the proteostasis machinery in the murine brain.…”

Primary cilia regulate the osmotic stress response of renal epithelial cells through TRPM3

“…of the mammalian kidney, and NaCl concentration in urine can vary widely, depending on the sodium content of the diet and the action of several mineralotropic hormones, including aldosterone (30). Urea is also a primary solute of urine; however, because of its (albeit low) membrane permeability, hyperosmolal urea does not activate the TonEBP-regulated osmotic stress response (28). Rather, it activates the phosphoinositide 3-kinase and MAP kinase pathways as an alternative cellular stress response mechanism, leading to Egr1 transcription (42,53).…”

Close Association of Carbonic Anhydrase (CA2a and CA15a), Na+/H+ Exchanger (Nhe3b), and Ammonia Transporter Rhcg1 in Zebrafish Ionocytes Responsible for Na+ Uptake

“…Therefore, FW fishes actively take up Na + and Cl − from their environment across the gill and skin epithelium (reviewed by Kirschner, 2004). The gill and skin contain a special type of ion-transporting epithelial cells, namely mitochondrion-rich cells (MRCs; also called ionocytes or chloride cells) which are rich in mitochondria and Na + –K + –ATPase, providing the driving force for active ion transport (Perry, 1997; Hirose et al, 2003; Evans et al, 2005; Hwang and Lee, 2007; Evans, 2008, 2010; Hwang, 2009; Lee et al, 2011; Dymowska et al, 2012; Kumai and Perry, 2012). The mechanism by which MRCs of FW fishes absorb Na + has been extensively studied in traditional model species such as tilapia, trout, salmon, eel, dace, and killifish, and at least three different pathways have been proposed (for a recent review see, Hwang et al, 2011): (1) electrogenic H + secretion by vacuolar-type H + -ATPase (H + -ATPase) provides driving force for Na + influx through an apical amiloride-sensitive Na + channel; (2) apical Na + /H + exchanger (Nhe 1 ) mediates entry of ambient Na + in exchange for intracellular H + equivalents; and (3) fish-specific Na + -Cl − cotransporter (Ncc) mediates electroneutral uptake of NaCl at the apical membrane of a subpopulation of MRCs (Hiroi et al, 2008).…”