Recent advances in understanding renal ammonia metabolism and transport

Weiner, I. David; Verlander, Jill W.

doi:10.1097/mnh.0000000000000255

Cited by 28 publications

(29 citation statements)

References 34 publications

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“…The appropriate renal response to metabolic acidosis is increased ammonia excretion. [25][26][27] In contrast, DCT-CA-SPAK mice excreted significantly less ammonia than did WT mice ( Figure 1). Impaired ammonia excretion was not due to impaired urine acidification, because urine pH did not differ significantly.…”

Section: Physiologic Datamentioning

confidence: 96%

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Mechanism of Hyperkalemia-Induced Metabolic Acidosis

Harris

Grimm

Lee

et al. 2018

JASN

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Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), the most common RTA observed, but the molecular mechanisms underlying the associated metabolic acidosis are incompletely understood. We sought to determine whether hyperkalemia directly causes metabolic acidosis and, if so, the mechanisms through which this occurs. We studied a genetic model of hyperkalemia that results from early distal convoluted tubule (DCT)-specific overexpression of constitutively active Ste20/SPS1-related proline-alanine-rich kinase (DCT-CA-SPAK). DCT-CA-SPAK mice developed hyperkalemia in association with metabolic acidosis and suppressed ammonia excretion; however, titratable acid excretion and urine pH were unchanged compared with those in wild-type mice. Abnormal ammonia excretion in DCT-CA-SPAK mice associated with decreased proximal tubule expression of the ammonia-generating enzymes phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase and overexpression of the ammonia-recycling enzyme glutamine synthetase. These mice also had decreased expression of the ammonia transporter family member Rhcg and decreased apical polarization of H-ATPase in the inner stripe of the outer medullary collecting duct. Correcting the hyperkalemia by treatment with hydrochlorothiazide corrected the metabolic acidosis, increased ammonia excretion, and normalized ammoniagenic enzyme and Rhcg expression in DCT-CA-SPAK mice. In wild-type mice, induction of hyperkalemia by administration of the epithelial sodium channel blocker benzamil caused hyperkalemia and suppressed ammonia excretion. Hyperkalemia decreases proximal tubule ammonia generation and collecting duct ammonia transport, leading to impaired ammonia excretion that causes metabolic acidosis.

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Section: Physiologic Datamentioning

confidence: 96%

“…Both are normally induced by metabolic acidosis. 25,26,28,29 We first examined PEPCK expression. Immunoblot analysis showed DCT-CA-SPAK significantly decreased expression ( Figure 2A).…”

Section: Response Of Proteins Involved In Pt Ammonia Generationmentioning

confidence: 99%

Mechanism of Hyperkalemia-Induced Metabolic Acidosis

Harris

Grimm

Lee

et al. 2018

JASN

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“…Rhbg and Rhcg are widely expressed on the plasma membranes of various mammalian organs such as the liver, kidney, gastrointestinal tract, and lung [ 8 – 12 ]. Rhbg transports both NH 3 and NH 4 + , whereas Rhcg only transports NH 3 [ 13 ]. Epithelial expression of RhCG mRNA has been reported in the testis, prostate, pancreas, and brain [ 8 ], and Rhcg plays a critical role in ammonium handling and pH homeostasis both in the kidney and in the male reproductive tract [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of tumor necrosis factor-α on the expression of the ammonia transporter Rhcg in the brain in mice with acute liver failure

Wen

Lü

et al. 2018

J Neuroinflammation

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BackgroundAmmonia and tumor necrosis factor-alpha (TNF-α) play important roles in the mechanisms of hepatic encephalopathy (HE). Rhesus glycoprotein C (Rhcg) is important for ammonia transport especially in the kidney. The aim of the present study was to investigate the role of Rhcg in the brain in acute liver failure (ALF) and the effect of TNF-α on Rhcg expression.MethodsALF mouse models were generated by treatment with d-galactosamine (D-GalN) and lipopolysaccharide (LPS), or D-GalN and TNF-α. ALF induction was blocked by pretreatment with anti-TNF-α IgG. The levels of serum TNF-α were determined by ELISA. Blood ammonia and brain ammonia concentrations were detected using an ammonia assay kit. The expression and distribution of Rhcg in the brain tissues of ALF mice were examined by western blotting, real-time PCR, immunohistochemical, and immunofluorescence analyses.ResultsSerum TNF-α levels were increased in the LPS/D-GalN group. Blood and brain ammonia were increased in the LPS/D-GalN- and TNF-α/D-GalN-induced ALF groups. Rhcg mRNA and protein levels were elevated in both ALF groups, consistent with the increase in blood and brain ammonia. Rhcg was mainly expressed in vascular endothelial cells and astrocytes. Pretreatment with anti-TNF-α IgG antibody downregulated Rhcg in brain tissues in the LPS/D-GalN group, prevented the occurrence of ALF, and reduced blood and brain ammonia levels in the LPS/D-GalN group.ConclusionTNF-α promoted the transport of ammonia from the blood to brain tissues and exacerbated the toxic effects of ammonia by upregulating Rhcg.

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“…6,9,10 The kidneys control the metabolic component of acid-base homeostasis through the process of net acid excretion. [11][12][13][14] Under basal conditions, the major mechanism of net acid excretion involves urinary ammonia excretion, 15 and in response to exogenous acid-loading, almost the entire change in net acid excretion occurs as a result of increased ammonia excretion. 11,12,15 However, the molecular mechanisms through which the kidneys recognize changes in acid-base status and alter ammonia metabolism are not well understood.…”

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NBCe1-A Regulates Proximal Tubule Ammonia Metabolism under Basal Conditions and in Response to Metabolic Acidosis

Lee

Osis

Harris

et al. 2018

JASN

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Renal ammonia metabolism is the primary mechanism through which the kidneys maintain acid-base homeostasis, but the molecular mechanisms regulating renal ammonia generation are unclear. In these studies, we evaluated the role of the proximal tubule basolateral plasma membrane electrogenic sodium bicarbonate cotransporter 1 variant A (NBCe1-A) in this process. Deletion of the NBCe1-A gene caused severe spontaneous metabolic acidosis in mice. Despite this metabolic acidosis, which normally causes a dramatic increase in ammonia excretion, absolute urinary ammonia concentration was unaltered. Additionally, NBCe1-A deletion almost completely blocked the ability to increase ammonia excretion after exogenous acid loading. Under basal conditions and during acid loading, urine pH was more acidic in mice with NBCe1-A deletion than in wild-type controls, indicating that the abnormal ammonia excretion was not caused by a primary failure of urine acidification. Instead, NBCe1-A deletion altered the expression levels of multiple enzymes involved in proximal tubule ammonia generation, including phosphate-dependent glutaminase, phosphoenolpyruvate carboxykinase, and glutamine synthetase, under basal conditions and after exogenous acid loading. Deletion of NBCe1-A did not impair expression of key proteins involved in collecting duct ammonia secretion. These studies demonstrate that the integral membrane protein NBCe1-A has a critical role in basal and acidosis-stimulated ammonia metabolism through the regulation of proximal tubule ammonia-metabolizing enzymes.

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Recent advances in understanding renal ammonia metabolism and transport

Cited by 28 publications

References 34 publications

Mechanism of Hyperkalemia-Induced Metabolic Acidosis

Mechanism of Hyperkalemia-Induced Metabolic Acidosis

Effect of tumor necrosis factor-α on the expression of the ammonia transporter Rhcg in the brain in mice with acute liver failure

NBCe1-A Regulates Proximal Tubule Ammonia Metabolism under Basal Conditions and in Response to Metabolic Acidosis

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