Pyk2 activation is integral to acid stimulation of sodium/hydrogen exchanger 3

Li, Shaoying; Sato, Soichiro; Yang, Xiaojing; Preisig, Patricia A.; Alpern, Robert J.

doi:10.1172/jci200418046

Cited by 81 publications

(89 citation statements)

References 20 publications

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“…Pyk2 is a cytoplasmic nonreceptor tyrosine kinase, which is activated by autophosphorylation when cells are grown in an acidified medium. 15,16 Phosphorylated Pyk2 directly activates cSrc, 15,16 which subsequently activates Rac1, a functional cytosolic subunit of NOX. 17,18 The NOX complex including Rac1 induces ROS production by transferring electrons from NAD(P)H to oxygen.…”

mentioning

confidence: 99%

Luminal Alkalinization Attenuates Proteinuria-Induced Oxidative Damage in Proximal Tubular Cells

Souma¹,

Abe²,

Moriguchi³

et al. 2011

Journal of the American Society of Nephrology

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alkalinization abrogates proteinuria-induced tubular damage, we studied a mouse model of protein-overload nephropathy. NaHCO 3 feeding selectively alkalinized the urine and dramatically attenuated the accumulation of O 2 ⅐ Ϫ -induced DNA damage and proximal tubular injury. Overall, these observations suggest that luminal acidity aggravates proteinuria-induced tubular damage and that modulation of this acidic environment may hold potential as a therapeutic target for proteinuric kidney disease.

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mentioning

confidence: 99%

Luminal Alkalinization Attenuates Proteinuria-Induced Oxidative Damage in Proximal Tubular Cells

Souma¹,

Abe²,

Moriguchi³

et al. 2011

Journal of the American Society of Nephrology

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“…Either an acid load or frank systemic metabolic acidosis (hypobicarbonatemia) leads to a decrease in proximal tubule cell pH, which activates prolinerich tyrosine kinase 2 (Pyk2, a pH sensor). 59 This is a direct specific effect because acidic solutions can activate Pyk2, but not the closely related focal adhesion kinase, in a cell-free system. 59 Pyk2 then activates c-Src.…”

Section: Adaptation To Metabolic Acidosismentioning

confidence: 99%

“…59 This is a direct specific effect because acidic solutions can activate Pyk2, but not the closely related focal adhesion kinase, in a cell-free system. 59 Pyk2 then activates c-Src. Both Pyk2 and c-Src activation are required for acid to activate NHE3 activity.…”

Section: Adaptation To Metabolic Acidosismentioning

confidence: 99%

“…Both Pyk2 and c-Src activation are required for acid to activate NHE3 activity. [59][60][61][62] Downstream from c-Src is endothelin-1 (ET-1) production and ET-1/ETB mediates acid stimulation of NHE3 involving exocytic insertion of NHE3 into the apical membrane. This process requires an intact cytoskeleton, 65 and is associated with NHE3 phosphorylation.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…Both Pyk2 and c-Src activation are required for acid to activate NHE3 activity. [59][60][61][62] Downstream from c-Src is endothelin-1 (ET-1) production and secretion by the proximal tubule. 53,63 The mechanism by which c-Src stimulates ET-1 secretion is not yet known.…”

Section: Adaptation To Metabolic Acidosismentioning

confidence: 99%

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

Bobulescu

Moe

2006

Seminars in Nephrology

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The kidney plays key roles in extracellular fluid pH homeostasis by reclaiming bicarbonate (HCO 3 − ) filtered at the glomerulus and generating the consumed HCO 3 − by secreting protons (H + ) into the urine (renal acidification). Sodium-proton exchangers (NHEs) are ubiquitous transmembrane proteins mediating the countertransport of Na + and H + across lipid bilayers. In mammals, NHEs participate in the regulation of cell pH, volume, and intracellular sodium concentration, as well as in transepithelial ion transport. Five of the 10 isoforms (NHE1-4 and NHE8) are expressed at the plasma membrane of renal epithelial cells. The best-studied isoform for acid-base homeostasis is NHE3, which mediates both HCO 3 − absorption and H + excretion in the renal tubule. This article reviews some important aspects of NHEs in the kidney, with special emphasis on the role of renal NHE3 in the maintenance of acid-base balance.Keywords sodium/hydrogen exchange; renal acidification; bicarbonate absorption The free hydrogen ion (H + ) concentration in body fluids is regulated exquisitely around 40 nmol/L (pH 7.40) whereas H + flux through the body greatly exceeds this magnitude. In a 70-kg human being at a basal state, normal metabolic and dietary acid production rate is about 50 to 70 mmoles/d and respiratory volatile acid production at the basal state is around 15,000 mmoles/d, with peak production at maximal exercise reaching 200 mmoles/min. The flux of H + through the organism over 24 hours is 8 orders of magnitude greater than the total pool of free H + in total body water (<2 μmoles). This remarkable homeostatic feat is accomplished by concerted efforts of extracellular and intracellular buffers, highly efficient ventilatory responses, metabolic functions of the liver, and renal ammoniagenic and solute transport mechanisms. For excretion of nonvolatile acid and base loads, the kidney assumes the pivotal role.A filtration-reabsorption nephron bears an exorbitant burden of having to reclaim a vast amount of valuable solutes indiscriminately dispensed in the filtrate; one of which of course is the approximately 4,000 mmoles of bicarbonate (HCO 3 − ) per day. The luminal acid disequilibrium pH implies that the predominant mode of HCO 3 − absorption involves H + secretion, although a small concomitant degree of direct HCO 3 − reabsorption cannot be excluded. 1 Two points are noteworthy. First, complete reclamation of the approximately 4,000 mmoles of filtered HCO 3 − forestalls a physiologic disaster but does not lead to net acid secretion. Further elaboration of H + into the urine is necessary. Second, whether the organism is catering to the The era of phenomenologic analysis was supplemented by gene-and protein-specific reagents when the first mammalian NHE was cloned by Sardet et al. 7 The relationship between mammalian NHE genetic sequence and those from a multitude of organisms is shown in Fig 2. Na + /H + exchange across lipid bilayers and proteins that sustain this function are universal in prokaryotic, animal, and...

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Molecular Mechanisms and Regulation of Urinary Acidification

Kurtz

2014

Comprehensive Physiology

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The H+ concentration in human blood is kept within very narrow limits, ~ 40 nM, despite the fact that dietary metabolism generates acid and base loads that are added to the systemic circulation throughout the life of mammals. One of the primary functions of the kidney is to maintain the constancy of systemic acid-base chemistry. The kidney has evolved the capacity to regulate blood acidity by performing three key functions: 1) reabsorb HCO3− that is filtered through the glomeruli to prevent its excretion in the urine; 2) generate a sufficient quantity of new HCO3− to compensate for the loss of HCO3− resulting from dietary metabolic H+ loads and loss of HCO3− in the urea cycle; and 3) excrete HCO3− (or metabolizable organic anions) following a systemic base load. The ability of the kidney to perform these functions requires that various cell types throughout the nephron respond to changes in acid-base chemistry by modulating specific ion transport and/or metabolic processes in a coordinated fashion such that the urine and renal vein chemistry is altered appropriately. The purpose of the article is to provide the interested reader with a broad review of a field that began historically ~ 60 years ago with whole animal studies, and has evolved to where we are currently addressing questions related to kidney acid-base regulation at the single protein structure/function level.

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Pyk2 activation is integral to acid stimulation of sodium/hydrogen exchanger 3

Cited by 81 publications

References 20 publications

Luminal Alkalinization Attenuates Proteinuria-Induced Oxidative Damage in Proximal Tubular Cells

Luminal Alkalinization Attenuates Proteinuria-Induced Oxidative Damage in Proximal Tubular Cells

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

Molecular Mechanisms and Regulation of Urinary Acidification

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