Site-specific regulation of organic osmolytes along the rat nephron

Schmolke, M.; Bornemann, A.; Guder, Walter G.

doi:10.1152/ajprenal.1996.271.3.f645

Cited by 18 publications

(29 citation statements)

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“…It has been reported that the distribution of sorbitol increases from the cortex to the papillary tip in mammalian kidneys (68,69). This is consistent with an increasing pattern of urea from the proximal tubule to the collecting duct.…”

Section: Discussionsupporting

confidence: 79%

Naturally Occurring Osmolytes Modulate the Nanomechanical Properties of Polycystic Kidney Disease Domains

Oberhauser

2010

Journal of Biological Chemistry

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Polycystin-1 (PC1) is a large membrane protein that is expressed along the renal tubule and exposed to a wide range of concentrations of urea. Urea is known as a common denaturing osmolyte that affects protein function by destabilizing their structure. However, it is known that the native conformation of proteins can be stabilized by protecting osmolytes that are found in the mammalian kidney. PC1 has an unusually long ectodomain with a multimodular structure including 16 Ig-like polycystic kidney disease (PKD) domains. Here, we used single-molecule force spectroscopy to study directly the effects of several naturally occurring osmolytes on the mechanical properties of PKD domains. This experimental approach more closely mimics the conditions found in vivo. We show that upon increasing the concentration of urea there is a remarkable decrease in the mechanical stability of human PKD domains. We found that protecting osmolytes such as sorbitol and trimethylamine N-oxide can counteract the denaturing effect of urea. Moreover, we found that the refolding rate of a structurally homologous archaeal PKD domain is significantly slowed down in urea, and this effect was counteracted by sorbitol. Our results demonstrate that naturally occurring osmolytes can have profound effects on the mechanical unfolding and refolding pathways of PKD domains. Based on these findings, we hypothesize that osmolytes such as urea or sorbitol may modulate PC1 mechanical properties and may lead to changes in the activation of the associated polycystin-2 channel or other intracellular events mediated by PC1. Polycystin-1 (PC1)2 is a large transmembrane protein, which, when mutated, cause autosomal dominant polycystic kidney disease (PKD), one of the most common lifethreatening genetic diseases, which is a leading cause of kidney failure (1). The available evidence suggests that PC1 acts as a mechanosensor, receiving signals from the primary (luminal) cilia, neighboring cells, and extracellular matrix and transduces them into cellular responses that regulate proliferation, adhesion, and differentiation that are essential for the control of renal tubules and kidney morphogenesis (1-4).PC1 is expressed along the renal tubule, where it is exposed to a wide range of concentrations of urea, from 5 mM in the proximal tubule to up to ϳ1 M in the collecting duct (5-7). Urea is known as a common denaturant that affects protein function by perturbing their structure (8). Several osmolytes have been found in the mammalian kidney that are known to counteract the effects of urea on proteins (9 -15). Among epithelial cells of the kidney medulla, the principal organic osmolytes include the polyols sorbitol and inositol, the methylamines betaine and glycerophosphocholine, and the amino acid taurine. Protecting osmolytes are found in all taxa (11,14). For example, cartilaginous fish concentrate trimethylamine N-oxide (TMAO), to offset the damaging effects of urea on protein function, and it is one of the best studied protecting osmolytes (e.g. 16 -20).The mecha...

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Section: Discussionsupporting

confidence: 79%

Naturally Occurring Osmolytes Modulate the Nanomechanical Properties of Polycystic Kidney Disease Domains

Oberhauser

2010

Journal of Biological Chemistry

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“…It has been proposed to be a volume-regulatory anion channel [81][82][83][84][85][86], an ion channel regulator [87][88][89][90], or possibly unrelated to cell volume regulation [18, [91][92][93][94][95][96][97][98][99][100][101]. The anion exchanger AE 1 of fish erythrocytes, but not of mammalian erythrocytes, confers an anion channel permeable not only to Cl -but also to the organic osmolyte taurine [102,193]. Regardless of the mechanism of action, additional channels must be operative in regulatory cell volume decrease.…”

Section: Regulatory Cell Volume Decrease (Rvd)mentioning

confidence: 99%

“…The osmolytes utilized by mammalian cells include polyalcohols such as sorbitol and inositol, methylamines such as glycerophosphorylcholine and betaine, amino acids such as glycine, glutamine, glutamate, aspartate, and taurine [47,174,178,179,[182][183][184][190][191][192][193], and amino acid derivatives.…”

Section: General Properties Of Osmolytesmentioning

confidence: 99%

The Diversity of Volume Regulatory Mechanisms

Lang

Busch²,

Völkl³

1998

Cell Physiol Biochem

289

233

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Mammalian cells utilize a wide variety of cell volume regulatory mechanisms. For rapid adjustment of cell volume cells release or accumulate ions through respective channels and transport systems across the cell membrane. The most widely used mechanisms of cell volume regulatory ion release include ion channels and KCl symport. Ion uptake is most frequently mediated by Na⁺ channels, Na⁺, K⁺, 2Cl^– cotransport, and Na⁺/H⁺ exchange. Chronic adjustment of cell osmolarity is accomplished by the formation or accumulation of organic osmolytes, molecules specifically designed to create intracellular osmolarity without interfering with cellular function. The most widely occurring osmolytes are sorbitol, inositol, glycerophosphorylcholine, betaine, taurine, and amino acids. The osmolytes are either synthesized by or transported into shrunken cells. During cell swelling osmolytes can be rapidly degraded or released. Any given cell may utilize several volume-regulatory mechanisms. Moreover, different mechanisms are utilized in different tissues. The diversity of cell volume regulatory mechanisms allows the cells to defend the constancy of cell volume against a myriad of challenges with relatively little impairment of cellular function.

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“…This regulation is independent of the amount of INPS (INO1 in yeast), which is not growthphase dependent (Robinson et al, 1996). In animals uptake and efflux of osmolytes, including myo-inositol, occurs according to interstitial tonicity (Schmolke et al, 1996a(Schmolke et al, , 1996b. The characteristics of inositol flux into and out of C6 cells, for example, are similar to those described for volume-regulatory sorbitol and taurine efflux in a number of cell types (Strange et al, 1993).…”

Section: Myo-inositol Unloading Extracellular Movement and Myo-inosmentioning

confidence: 99%

Myo-Inositol-Dependent Sodium Uptake in Ice Plant1

Nelson¹,

Koukoumanos²,

Bohnert

1999

Plant Physiology

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In the study reported here we found increased phloem transport of myo-inositol and reciprocal increased transport of sodium and inositol to leaves under stress. To determine the relationship between increased translocation and sodium uptake, we analyzed the effects of exogenous application of myo-inositol: The NaCl-inducible ice plant myo-inositol 1-phosphate synthase is repressed in roots, and sodium uptake from root to shoot increases without stimulating growth. Sodium uptake and transport through the xylem was coupled to a 10-fold increase of myo-inositol and ononitol in the xylem. Seedlings of the ice plant are not salt-tolerant, and yet the addition of exogenous myo-inositol conferred upon them patterns of gene expression and polyol accumulation observed in mature, salt-tolerant plants. Sodium uptake and transport through the xylem was enhanced in the presence of myo-inositol. The results indicate an interdependence of sodium uptake and alterations in the distribution of myo-inositol. We hypothesize that myo-inositol could serve not only as a substrate for the production of compatible solutes but also as a leaf-to-root signal that promotes sodium uptake.Current strategies for improving tolerance to sodium stress, whether based on breeding or transformation, rely primarily on the production of low-M r solutes and on enhancing radical-scavenging enzyme systems (Tarczynski et al

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Site-specific regulation of organic osmolytes along the rat nephron

Cited by 18 publications

References 0 publications

Naturally Occurring Osmolytes Modulate the Nanomechanical Properties of Polycystic Kidney Disease Domains

Naturally Occurring Osmolytes Modulate the Nanomechanical Properties of Polycystic Kidney Disease Domains

The Diversity of Volume Regulatory Mechanisms

Myo-Inositol-Dependent Sodium Uptake in Ice Plant1

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