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Highlights from the literature

Nominated by Olaf Andersen
Editor, Journal of General Physiology
Cornell University
sparre{at}med.cornell.edu

Question: What underlies the different Ca²⁺ dependencies of insulin-granule exocytosis?

Background: Glucose is the major physiological inducer of Ca²⁺-dependent insulin secretion from pancreatic ß-cells. However, the Ca²⁺ sensitivity of insulin-granule exocytosis is reported to vary widely depending on the experimental paradigm employed. A similar disparity in the Ca²⁺ sensitivity of exocytosis in adrenal chromaffin cells has recently been reported. They contain a highly Ca²⁺-sensitive pool (HCSP) of granules that respond to low levels of Ca²⁺. Therefore, efforts were focused on determining whether insulin-secreting cells have a similar HCSP of granules in addition to the readily releasable pool (RRP) that has lower sensitivity to Ca²⁺.

Observations: Two complementary studies by Yang and Gillis and Wan et al. determined that there is a HCSP of granules in rat insulin-secreting insulinoma and ß-cells in addition to the RRP and reserve pool. Yang and Gillis showed that the HCSP can be enhanced by glucose, cAMP, and a phorbol ester. The cAMP and phorbol ester responses were mediated by PKA and PKC, but glucose increased the size of the granule pool independently of PKA and PKC activation. Using measures of kinetic release, they found that the granules from both the RRP and HCSP have similar fusion kinetics and morphology. Wan et al. also saw PKA- and PKC-dependent increases in the HCSP in response to phorbol esters and forskolin. In addition, they reported that the HCSP granules were released by Ca²⁺ increases throughout the cytosol, as opposed to localized increases, suggesting that the HCSP vesicles are not colocalized with Ca²⁺ channels. Both groups found the effects of PKC and PKA to be nonadditive, thus implicating a convergence of mechanisms.

Significance: The presence of HCSP in ß-cells explains how a phorbol ester can stimulate insulin secretion when glucose levels are subthreshold. Thus, rather than increasing the Ca²⁺ sensitivity of the secretory mechanism, as was proposed 20 years ago, they increase the size of the HCSP. This represents a novel mechanism for the control of insulin secretion and significantly contributes to our under-standing of insulin homeostasis.

Nominated by Michael Caplan
Yale University School of Medicine
michael.caplan{at}yale.edu

Question: Can the precursors to the complexes formed during exocytosis be modeled in vivo?

Background: Exocytosis is a fundamental physiological process that is catalyzed by three proteins collectively known as SNAREs: syntaxin (Syx), synaptosome-associated protein of 25 kDa (SNAP25), and synaptobrevin (Syb). These three proteins assemble into a core complex with four parallel -helices that pull the vesicular and plasma membranes together. One helix is formed by Syx, one by Syb, and two by the SNARE motifs of SNAP25: SN1 and SN2 (note that two copies of Syx can form a binary complex with SNAP25 also). Although partial SNARE complexes have been observed in solution, suggesting that the complexes form in steps, none has been observed in vivo.

Observations: An and Almers used fluorescent SNAP25 to identify its entry into a binary SNARE complex with Syx. The effects of either mutating the SN1 or deleting the SN2 SNARE motif region of SNAP25 in vitro resulted in an inability of SNAP25 to enter a SNARE complex formation. These findings were then explored in vivo. SNARE complex formation was normal and Ca²⁺ dependent when the wild-type SNAP25 probe and Syx were used. However, upon mutation of SN1, complex formation was prevented. Surprisingly, the SN2 deletion induced a biphasic effect whereby at low concentrations Syx increased the appearance of SNARE (a Syx-SN1 complex, partial SNARE), but higher Syx concentrations produced a "silent" complex that was undetectable. Next, they pursued this Syx-SN1 interaction and caused a mutation known to prevent Syx and SN1 complex formation. Not only did this fail to attenuate formation of the Syx-SN1 complex, but it appears to have prevented the formation of the silent complex and promoted the retention of Syx-SN1 complex formation even at high concentrations of Syx.

Significance: These findings provide an in vivo model of Ca²⁺-dependent exocytosis that involves the formation of precursors and explains the partial SNARE complexes observed in solution. Elucidation of this process is of universal interest but may be of particular interest to those who study synaptic plasticity.

Nominated by Michael Caplan
Yale University School of Medicine
michael.caplan{at}yale.edu

Question: Does modulation of PKC activity in the prefrontal cortex (PFC) affect executive function?

Background: Empirical studies of the PFC in humans and animals have demonstrated a pattern of connectivity that places the PFC in a unique anatomic position to perform executive functions and modulate limbic information. Thus proper functioning of the PFC is critical for conscious, goal-directed behavior guided by experience. Predictably, then, prefrontal dysfunction is seen in several disease states such as bipolar disorder and schizophrenia. These disorders have also been associated with dysregulation of PKC signaling, because lithium (Li) and valoproate (Val), two pharmacological treatments for bipolar patients, attenuate PKC activity. However, a direct association between PKC signaling and prefrontal cortical cognitive function is lacking.

Observations: Birnbaum et al. found that PKC activation, either directly or in-directly [via ₁-adrenergic receptor (1R) stimulation or exposure to the pharmacological stressor FG7142], results in increased PKC signaling. The effects of these PKC activators on cognitive tasks known to be dependent on proper PFC functioning were evaluated in rodents (PFC infusions) and monkeys (systemic administrations). Exposure to any of the PKC activators resulted in specific impairment of PFC executive functions. Moreover, chronic Li or Val prevented the direct pharmacological activation of PKC, and both Li and Val pretreatment prevented the deficits in cognitive performance following 1R agonist exposure in monkeys. Finally, electrophysiological recordings of primate PFC neurons during task performance revealed an attenuation of the normal task-related increase in firing activity after PKC activation. Notably, many of the PKC-induced deficits in cognitive performance, as well as the reductions in firing activity, were reversible with a PKC inhibitor.

Significance: These data demonstrate that excessive PKC activity in the PFC can cause impairments in cortical cognitive functions. This study has several implications for the etiology and treatment of bipolar disorder as well as stress-induced cognitive dysfunction. It would be interesting to see if a psychological stressor would induce cognitive dysfunction via a similar PKC-dependent pathway.

Nominated by Michael Caplan
Yale University School of Medicine
michael.caplan{at}yale.edu

Question: Can the cause of a cluster of metabolic defects be linked to a single mutation?

Background: Metabolic syndrome (MS) is the phenotypic clustering of various combinations of hypercholesterolemia (HC), hypertriglyceridemia, hypomagnesemia (HM), diabetes, insulin resistance, and obesity. The origin of MS is unknown, and although there are genetic mutations known to account for some of these abnormalities individually, none is so inclusive as to account for all of these phenotypes.

Observations: Wilson et al. evaluated a line of kindred (K129) with a high prevalence of HM, HC, and hypertension. They found that affected mothers were responsible for transmitting these traits to their offspring, a hallmark of inheritance via the mitochondrial genome. They thus focused on the mitochondrial genome in search of a polymorphism and found 14. Only one of these variants was previously unknown and present in the maternal lineage of K129. Biochemical data indicated that a mutation at this position significantly impairs ribosome binding, which provides evidence that this mutation has functional consequences. K129 also presented with other features characteristic of mitochondrial mutation in others, including attenuated ATP production.

Significance: This work emphasizes that a single mutation can cause an array of abnormalities and provides some potential insight into the role of mitochondrial dysfunction in hypertension and HC. Although K129 did not have all of the abnormalities previously linked to dysfunctional mitochondria, the possibility remains that all of the phenotypes associated with MS could be caused by such a mutation.

Nominated by Reiko Fitzsimonds
Yale University School of Medicine
reiko.fitzsimonds{at}yale.edu

Question: Do icilin and menthol activate the transient receptor potential (TRP) channel TRPM8 through a similar mechanism?

Background: TRP channels are non-selective Ca²⁺-permeable cation channels that are pharmacologically and genetically implicated in the detection and transduction of sensory stimuli. The TRP channel TRPM8 is one such channel that functions as a thermosensor. It is activated by reductions in ambient temperatures and by chemicals that produce psychophysical sensations of cold such as icilin, menthol, and eucalyptol. Although available evidence suggests that TRPM8 activation by menthol occurs in the absence of Ca²⁺, icilin-induced TRPM8 activation apparently requires Ca²⁺. This suggests that icilin-induced TRPM8 activation may require simultaneous activation by a coagonist.

Observations: Maximal activation of the TRPM8 channel by icilin was associated with a significant temporal delay compared with menthol or cold. Further probing revealed that icilin acts as a partial agonist at TRPM8 channels in Ca²⁺-free conditions, causing an increase in intracellular Ca²⁺ from either intracellular stores or Ca²⁺ translocation via TRPM8 channels. Thus, upon icilin-induced buildup of intracellular Ca²⁺ concentrations, icilin causes full activation of the TRPM8 channel. In addition to being an icilin-selective coagonist, Ca²⁺ was also necessary for TRPM8 desensitization. The functional domain of the TRPM8 channel-icilin interaction was also defined. These efforts revealed three residues in the cytoplasmic loop that interact with icilin and account for the differential sensitivity to icilin.

Significance: The mechanism responsible for TRPM8 activation by menthol and cold is distinct from that of icilin. The coincidence of icilin- and Ca²⁺-induced TRPM8 channel activation represents a novel system that increases the information capacity of this channel. The elucidation of this mechanism could conceivably lead to the identification of previously unappreciated endogenous stimuli that also require concomitant inputs for activation of TRPM8 or other members of the TRP channel family.

Nominated by Reiko Fitzsimonds
Yale University School of Medicine
reiko.fitzsimonds{at}yale.edu

Question: How does manipulation of the actin-binding protein neurabinl (Nrbl) affect spine morphogenesis and synapse formation?

Background: Dendritic spine motility is hypothesized to promote synapse formation because periods of high motility coincide with synapse formation. The proteins Nrbl and spinophilin/neurabinll (Nrbll) are prominent players in spine morphogenesis and may be involved in the regulation of spine number and shape. Both proteins have NH₂-terminal F-actin binding domains, protein phosphotase-1 (PP1) binding domains, PDZ domains (involved in targeting molecules to membrane sites), and COOH-terminal coiled-coil domains (supporting homodimerization and heterodimerization). Previous models also suggest that nascent spines are stabilized by the formation of synapses. Thus the relationship between spine actin dynamics, spine motility, spine morphogenesis, and synapse formation was explored.

Observations: Zito et al. started by showing that the F-actin binding domain of Nrbl [Nrbl-(1—287)], and not the PP1 binding domain, PDZ domain, or coiled-coil domain, was required for its proper localization in spines and spine morphogenesis. Additionally, Nrbl-(1—287) caused actin polymerization and increased spine density, length, motility, and exploration without affecting spine lifetime or turnover. Moreover, over-expression of this truncated protein stimulated the formation of new synapses. However, this increase in synapse number caused an equivalent decrease in both -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated and N-methyl-D-aspartate receptor-mediated currents, thus downregulating synaptic strength and maintaining a constant level of total synaptic input. Another binding domain is also described that potentiates Nrbl-induced morphogenesis.

Significance: These results provide new insights into Nrbl function and strongly support the hypothesis that synaptogenesis is regulated by spine actin motility. This evokes several intriguing questions about the role of actin regulation in the processes of learning and memory and cognitive disorders and provides new targets to manipulate empirically.

Nominated by James Hicks
University of California Irvine
jhicks{at}uci.edu

Question: What is the cardiovascular status of the crucian carp (Carassius carassius) during periods of anoxia?

Background: Prolonged anoxia can be fatal for many animals, whereas for others it is a natural physiological process that can persist for months at low temperatures. This ability to withstand anoxia requires a balancing of the energy supply and a mechanism to buffer end-product buildup associated with anaerobic respiration. It has been known for some time that this is accomplished in most animals by there being an obligatory decrease in cardiovascular output and autonomic control. However, although their cardiovascular status and control are unknown, the crucian carp is unusual in that during anoxic exposure cellular energy demands are supplied via glycolysis, but unlike most other vertebrates (which produce lactate as the metabolic end point), the carp produces ethanol.

Observations: Stecyk et al. explored the cardiovascular status and control of these fish under anoxic conditions. There was an initial adjustment period upon exposure to anoxic conditions, but cardiac output, heart rate, stroke volume, cardiac power output, and respiration rate all returned to preanoxic levels by day 2. Autonomic cardiovascular control was also pharmacologically evaluated; tonic -adrenergic vasoconstriction as well as inhibitory cholinergic and excitatory ß-adrenergic tones were maintained during the anoxic period. In contrast, ventral aortic blood pressure and peripheral vascular resistance were significantly blunted, indicative of vasodilatation.

Significance: The study provides an interesting example of a physiological adaptive mechanism in response to an extreme environmental stress, in this case anoxia. Whereas most anoxic hearts fail within minutes or compensate by depressing their activity or autonomic control, the C. carassius heart tolerates anoxia and maintains cardiac output without relinquishing autonomic control. The authors speculate that the unusual tolerance of the heart to anoxia may be because of a mechanism that prevents ethanol accumulation and even intoxication in tissues.

Nominated by Baruch Kanner
Hebrew University Hadassah Medical School
kannerb{at}cc.huji.ac.il

Question: What can the three-dimensional structure of the glutamate transporter elucidate about the mechanism of substrate transport?

Background: There are five subtypes of sodium-dependent glutamate transporters. These integral membrane proteins are localized on neurons and glial cells, where they are responsible for maintaining basal levels of extracellular L-glutamate (Glu) in the synaptic cleft, which prevents excitotoxicity. Although a plethora of functional data exists, the structure of the transporter and the mechanism that allows the counter-transport of Glu and three Na⁺ ions intracellularly and one K⁺ ion extra-cellularly has remained elusive.

Observations: Yernool et al. crystallized a Glu transporter homolog from Pyrococcus horikoshii (GltPh), described its topology, and proposed a novel mechanism for flux coupling. The GltPh exists as a "bowl-shaped" trimer that has an extracellular concave hydrophilic aqueous basin with three Glu binding sites and a pointed base facing the intracellular milieu. Each of the promoters has eight transmembrane domains and two helical hairpins (HP1 and HP2), which are implicated in substrate binding and transport. HP1 is hypothesized to form the substrate-binding pocket and intracellular gate, whereas HP2 is hypothesized to contain the sodium-binding site and form the extracellular gate of the reentrant loops. In their alternating-access model, coordinated but distinct substrate-dependent conformational changes occur between HP1 and HP2 that allow substrate translocation.

Significance: On the basis of the structure of the GltPh, Yernool et al. provide a feasible gating mechanism for substrate translocation that is divergent from previous theories. Although there is still much to be determined about the molecular mechanism of Glu transport, this represents an important step forward. Further understanding of the glutamatergic system is essential, because its dysfunction is implicated in the pathology of several neurological diseases, including but not limited to Parkinson disease, Alzheimer disease, epilepsy, Huntington chorea, schizophrenia, and depression.

Nominated by Eve Marder
Editor, Journal of Neurophysiology
Brandeis University
marder{at}brandeis.edu

Question: Can a better model be developed to understand population phenomena in thalamocortical neuronal assemblies?

Background: The cortical neurons of the cerebral cortex are organized into columns. These cortical columns are complex processing and distributing units that link a number of inputs and outputs by means of overlapping internal processing chains. These networks are characterized by several phenomena, including persistent gamma oscillations, sleep spindles (cellular oscillations), synchronized population bursts (similar to seizure activity), and population bursts with very fast oscillations. Until now, models of thalamocortical circuits have used a relatively small number of cells with the capacity to mimic only a single firing behavior and usually do not include electrical coupling. However, gap junctions and chemical synapses are thought to cooperate in generating a variety of population phenomena. This work was an effort to understand the behavior of the cortical neuron network and how they generate population phenomena, including seizures and synchronized oscillations.

Observations: Traub et al. describe a thalamocortical column model that was developed with over 3,500 cells, at least eight different cell types with multiple compartments, chemical synaptic and gap junction-mediated cell-cell interactions, and various intrinsic currents. Importantly, this model displayed several of the network behaviors seen previously in neuron populations, including thalamocortical sleep spindles, synchronized population bursts (electrographic seizures), very fast oscillations, and persistent gamma oscillations. The electrical coupling between axons was determined to be necessary for persistent gamma oscillations. This electrical coupling and the degree of recurrent synaptic excitation between spiny stellate cells both appear to have a role in epileptogenic events.

Significance: In an effort to understand the physiology of network oscillations and epileptogenesis, the authors developed the largest thalamocortical network model to date with several more anatomic and physiological features than any previous model. This computational model provides a more complete model to probe further how intrinsic cell properties, chemical synapses, and gap junctions cooperate to shape population phenomena and may become a new classic in building large-scale models of brain circuits.

Nominated by Peter Meier-Abt
University of Zurich
meierabt{at}kpt.unizh.ch

Question: What structural characteristics of P-glycoprotein (P-gp) can be resolved from its three-dimensional structure?

Background: P-pg is a plasma membrane ATP binding cassette (ABC) transporter implicated in many genetic disorders and drug resistance of cancer cells and pathogens. Several studies of bacterial ABC transporters have revealed four domains, including two transmembrane domains each consisting of six transmembrane -helices. Studies of eukaryotic ABC transporters have revealed that large-scale conformational changes mediate substrate transport, but their structure is still unknown.

Observations: Rosenberg and co-workers used cryoelectron crystallography to obtain the three-dimensional structure of P-gp. This ABC transporter has the characteristic two transmembrane domains, each with six membrane-spanning -helices in a pseudo-twofold symmetry. Five of the -helices are symmetrical, whereas the sixth is not. The asymmetry is attributed to bound nucleotide-induced conformational changes, which is in agreement with lower-resolution negatively stained crystals grown in the presence of nucleotide. Four additional densities are described, one of which appears to be the major glycosylated extracellular loop of P-gp and two of which appear to be the hydrophilic nucleotide-binding domains on the intracellular side.

Significance: This is the first three-dimensional description of a nucleotide-bound asymmetrical P-gp with enough resolution to describe the packing of the transmembrane -helices. This description will be important for molecular modeling of P-pg, elucidating a mechanism of substrate transport, and understanding drug resistance.

Nominated by Pontus Perrson
Editor, American Journal of Physiology-Regulatory,
Integrative, and Comparative Physiology
Humboldt University
pontus.perrson{at}charite.de

Question: Does maternal protein restriction (MPR) lead to diabetes in female offspring late in life?

Background: Both genetic and environmental factors are hypothesized to play roles in diabetes susceptibility, insulin resistance, and other abnormalities associated with the metabolic syndrome. An environmental factor suggested to have an impact on susceptibility to these disorders is poor fetal growth. One extensively studied animal model of early growth retardation is MPR in rats. Whereas 15-month-old male offspring have impaired glucose tolerance and 17-month-old males have diabetes, female offspring at either stage show no signs of metabolic dysfunction. Additionally, MPR male rats show molecular indications that the insulin-signaling pathway is also affected.

Observations: Female rats live longer than male rats. Therefore, this study was done on MPR female rats at 21 months of age. These MPR females had normal glucose tolerance, but fasting insulin levels and the insulin response to glucose challenge were both significantly higher than controls. In addition, there was a decrease in the expression levels of muscle PKC-, which is thought to influence the ability of insulin to stimulate glucose uptake, and a decrease in phosphatidylinositol 3'-kinase proteins, which are implicated as being crucial for the metabolic activities of insulin in intra-abdominal fat.

Significance: These results suggest that MPR female rats are subject to an age-dependent onset of hyperinsulinemia and reduction in insulin-signaling proteins. As noted by Fernandez-Twinn et al., because the proteins reported here to be affected by MPR are also aberrant in human diabetics, they may be useful as early indicators of diabetic risk in male and female low-birth-weight individuals.

Nominated by Ulrich Pohl
Ludwig-Maximilians-Universitat Munchen
upohl{at}lmu.de

Question: Can thymosin-ß4 promote cardiac repair after a myocardial infarction?

Background: Cardiac stem cells are implicated in the maintenance of cardiomyocytes under basal physiological conditions but are unable to mitigate myocardial damage after an acute coronary occlusion. Isolated stem cells may improve myocardial function, but technical issues have prevented their widespread clinical use in cardiac regeneration. Thus the manipulation of cardiac developmental regulatory pathways is being explored. Thymosin-ß4 is a G-actin-sequestering peptide involved in cell migration and survival during cardiac morphogenesis that has also been shown to promote skin and corneal wound healing. Its potential role in cardiac wound repair is unknown.

Observations: Thymosin-ß4 was found to induce cardiac cell migration and survival in cultured embryonic cardiomyocytes. The proteins PINCH (a widely expressed focal adhesion protein) and integrin-linked kinase (ILK), both of which are essential for cell migration and survival, interacted intracellularly with thymosin-ß4 to induce these prophylactic effects independently of actin polymerization. These effects were conserved in vivo, as demonstrated by the fact that myocardial infarctions induced in mice were improved by thymosin-ß4 treatment via ILK activation, causing reduced scarring and preservation of myocardium after infarction.

Significance: These data reveal a novel mechanism through which thymosin-ß4 affects cellular functions, i.e., its ability to preserve myocardium after infarction. The mechanism(s) underlying this ability will require further research but the potential clinical application of modulating thymosin-ß4 levels to protect against cardiac injury is an enticing end point.

Nominated by Ulrich Pohl
Ludwig-Maximilians-Universitat Munchen
upohl{at}lmu.de

Question: Can mast cells influence the ability of endothelin-1 (ET-1) to induce pathology?

Background: Mast cells are tissue-residing cells of hematopoietic origin with granules that contain a variety of inflammatory mediators such as histamine, heparin, and proteolytic enzymes. ET-1 is a vasoconstrictor peptide that has been implicated in diverse physiological and pathological processes, including vascular changes associated with sepsis. There is a multifaceted relationship between mast cells and the ET-1 system, because mast cells can produce ET-1, can express ET receptors, are subject to ET-1- and endothelin-A receptor- (ET_A) dependent activation, and release the proteases chymase and carboxypeptidase A (CPA) upon degranulation, which can degrade ET-1. Both the pathology of some disorders and optimal host defense against bacterial infections are mediated by mast cells, and ET-1 has been implicated in many of the same settings. Therefore, understanding the significance of the interactions of ET-1 and mast cells in vivo is potentially important.

Observations: Maurer et al. show that activation of mast cells via ET_A in vivo results in a decrease in the levels of ET-1 (via a negative-feedback loop). Moreover, mast cells attenuated ET-1-induced pathology in vivo. The mast cell-dependent reduction in ET-1-induced pathology was a degranulation-dependent phenomenon in which chymase, not CPA, had a major role. Activation of this same pathway also contributed to survival during cecal ligation and puncture (CLP), an acute bacterial infection of the peritoneal cavity. In addition to ET_A, the endothelin-B receptor and other factors also may have contributed to mast cell activation by ET-1. However, activation of mast cells via ET_A appeared to be required for optimal expression of host defense, and optimal survival, after CLP.

Significance: These findings provide direct in vivo evidence that mast cells can promote homeostasis by limiting the toxicity of the endogenous substance ET-1. Given that ET-1 and mast cells are implicated in a host of other pathological conditions such as hypertension, atherosclerosis, asthma, and so forth, understanding the complex interactions of ET-1 and mast cells is of widespread interest.

Nominated by Michael Romero
Case Western Reserve University
mfr2{at}po.cwru.edu

Question: What can we learn about boron homeostasis in animal cells by using the recently cloned borate transporter?

Background: Borate is an essential micronutrient in plants, and although some role in animal cell growth has been reported, boron homeostasis in animal physiology has not been extensively explored. It was recently discovered that boron does not enter plant cells via passive diffusion; it enters via a boron transporter. This led to the cloning of a mammalian boron transporter (BTR1) whose expression appeared to be limited to the kidneys and salivary glands. Until this report, little else was known about boron homeostasis and boron transporter physiology in animals.

Observations: BTR1 was renamed NaBC1 after several transport properties indicated that it functions as a selective voltage-regulated electrogenic Na⁺-coupled borate cotransporter in the presence of borate. There is a shallow inward rectification associated with borate/Na⁺ influx and a steep outward rectification when mediating efflux. However, in the absence of borate NaBC1 functions as a Na⁺- and H⁺-permeable channel. RT-PCR analysis of NaBC1 indicated that it was ubiquitously expressed in all cell types probed. Moreover, at low concentrations borate activated the MAPK pathway, stimulating cell growth and proliferation, whereas at high concentrations it caused cell death. Finally, reducing the expression of NaBC1 caused inhibition of proliferation, suggesting a direct link between the two.

Significance: This work provides evidence that NaBC1 is a central regulator of cellular borate homeostasis and that NaBC1 is important in mediating the effects of borate on cell growth and proliferation; it also provides us with an understanding of the mechanism of borate transport by NaBC1. Given the importance of boron in plants and animals, the most significant contribution of these studies is an approach to studying the role of borate in animal physiology.

Nominated by Jeff Sands
Editor, American Journal of Physiology-Renal
Physiology
Emory University School of Medicine
jsands{at}emory.edu

Question: What effect does chronic inhibition of angiotensin (ANG) II generation by proximal tubules have on proximal fluid reabsorption and tubuloglomerular feedback responses?

Background: The renin-angiotensin system is an important regulator of extracellular volume and blood pressure. Renin, a proteolytic enzyme, is secreted by the kidney to catalyze ANG I release from the renin substrate angiotensinogen. ANG I is then cleaved by angiotensin-converting enzyme (ACE) to form ANG II. In addition to ANG II being systemically generated, it can also be formed by other tissues, including the kidneys. In an effort to understand the significance of ANG II formation in the proximal tubules, mice with plasma ACE but without any tissue-associated ACE (ACE 2/2) have been generated. This causes a decrease in blood pressure, which has then been corrected in a second line of mice that ectopically express the ACE gene in the liver (ACE 3/3).

Observations: In this set of experiments, the effects of chronically inhibiting ANG II formation by proximal tubules on proximal fluid reabsorption and tubulo-glomerular feedback responses were explored. A variant of the ACE 3/3 strain was generated in which one ACE allele was null and the other targeted ACE expression to the liver (ACE 1/3). These mice have normal blood pressure, and, like ACE 2/2 and ACE 3/3 mice, lack endothelial ACE expression. The absence of ACE in the proximal tubule brush border did not affect the relation between glomerular filtration rates and fluid reabsorption in ACE 1/3 or ACE 2/2 mice. However, ACE generated by renal tissue was shown to be important in the regulation of tubuloglomerular feedback because ACE 1/3 mice had a markedly reduced response.

Significance: The inability of the proximal tubules to produce ANG II was not associated with inhibition of proximal fluid transport. These findings are in conflict with the inhibitory effect of acutely reducing local ANG II formation on fluid reabsorption. With so many regulatory inputs of proximal fluid transport, this discrepancy is theorized to be because of the chronicity of ANG II blockade and an apparent compensatory mechanism that normalizes fluid re-absorption.

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