Physiologic regulation of soluble Klotho levels by systemic acid/base status
全身酸/碱状态对可溶性 Klotho 水平的生理调节
基本信息
- 批准号:10618852
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAcidosisAcidsAdenineAlkaliesAlkalinizationAmericanAnimal ModelAtrophic condition of skinBicarbonatesBilateralBloodCalcium-Sensing ReceptorsCellsCharacteristicsChemicalsChronicChronic Kidney FailureCirculationCitratesClinical ResearchClinical TrialsContralateralCultured CellsDASH dietDialysis procedureDietDiseaseDisease ProgressionDisease modelDistal convoluted renal tubule structureDivalent CationsEarly treatmentEffectiveness of InterventionsEnd stage renal failureEndothelinEnvironmentFamilyGoalsHealthHeart HypertrophyHumanHuman VolunteersInflammationInjury to KidneyIschemiaKidneyKidney DiseasesKidney FailureKnockout MiceLigandsLinkMeasuresMediatingMembrane MicrodomainsMetabolismModelingMultiprotein ComplexesMusNephrectomyOralParathyroid glandPathway interactionsPatientsPatternPeptidesPhenotypePhysiologicalPremature aging syndromeProductionProductivityProteinsPublic HealthRattusReceptor ActivationReceptor SignalingRegulationRenal TissueRenal functionRenal tubule structureRenin-Angiotensin-Aldosterone SystemReperfusion TherapyScaffolding ProteinSerumSmall Interfering RNASodium BicarbonateSourceSpecificityStructure of renal veinSupplementationSystemTestingTissuesTransplantationUrineVascular DiseasesVascular calcificationVeteransWorkagedalkalinitybasecalcificationcoronary fibrosisdisease phenotypeendothelial dysfunctionfallsfeedingfunctional lossin vivokidney cortexkidney fibrosisknock-downloss of functionmouse modelnovelpreservationpreventreceptorrenal calciumresponsesarcopeniatissue/cell culturevolume hypertension
项目摘要
Chronic kidney disease (CKD) frequently progresses to end-stage renal disease accompanied by complications
including cardiac hypertrophy, accelerated vascular disease, ectopic calcification, endothelial dysfunction,
osteodystrophy, sarcopenia, skin atrophy, and renal fibrosis. Factors including hypertension, volume-overload,
acidosis, chronic low-grade inflammation, disordered Ca and PO4 metabolism, elevated PTH and FGF23 levels,
and reduced circulating Klotho (sKlotho) levels are associated with CKD. HCO3 supplementation or alkaline
diets (eg. DASH diet) slow progression of CKD even in stages 3 and 4. The mechanism(s) by which HCO3
supplementation or alkaline diets work are unknown. The goal of these studies is to identify physiologic
mechanisms that can slow or reverse the course of CKD. sKlotho is normally produced by the kidney and
released into the circulation, preserves renal function, and prevents many of the systemic complications of renal
failure. As renal disease progresses serum and urine sKlotho levels fall, and patients acquire characteristics
resembling the premature aging phenotype of Klotho-/- mice. The kidney is the source of sKlotho as demonstrated
by findings that Klotho levels are high in the renal vein, bilateral nephrectomy lowers sKlotho, and mice with
kidney-specific Klotho deletion have patterns of disease that are phenotypically indistinguishable from Klotho-/-
mice. Possible physiologic mechanisms by which sKlotho levels might be regulated have not been defined. We
discovered that in intact mice and rats, mouse renal cortical homogenates, and cultured cells, calcium-sensing
receptor (CaSR) activation increases sKlotho levels via ADAM10-mediated shedding. The ability of ligands to
activate the CaSR is modified by pH with an alkaline pH environment increasing, and an acid pH environment
decreasing CaSR signaling. We found that an alkali load increases CaSR signaling and sKlotho in mice and rats,
and that an alkaline milieu increases Klotho shedding in mouse kidney homogenates and cultured cells in a
CaSR-dependent manner, and that oral K citrate for 72 hrs increases serum and urine Klotho in human
volunteers. These results define a novel physiologic mechanism for regulation of sKlotho levels by the renal
CaSR and pH. We hypothesize that acidosis accelerates, and alkalinization slows the rate of loss of renal
function in CKD because acidosis decreases, and alkalinity increases renal CaSR-stimulated Klotho
shedding from the kidney. The hypothesis will be developed with studies in: 1) mice, CaSR-/- mice, renal
homogenates, cultured cells, that will demonstrate that renal Klotho shedding is regulated by the CaSR in
response to CaSR ligands and pH; 2) CKD disease models to show that alkali treatment increases sKlotho levels
and reduces renal injury and cardiac hypertrophy, and 3) renal tissue and cultured cells to define the mechanisms
that permit the CaSR, Klotho, and ADAM10 to interact focusing on the C8 tetraspanin family.
慢性肾脏疾病(CKD)经常进展为终末期肾脏疾病,并伴有并发症
包括心脏肥大、加速的血管疾病、异位钙化、内皮功能障碍
骨营养不良、肌肉减少症、皮肤萎缩和肾纤维化。包括高血压,容量超负荷,
酸中毒、慢性低度炎症、Ca和PO 4代谢紊乱、PTH和FGF 23水平升高,
并且降低的循环中的sKlotho(sKlotho)水平与CKD相关。HCO 3补充或碱性
饮食(例如,DASH饮食)减缓CKD的进展,即使在第3和第4阶段。HCO 3的作用机制
补充或碱性饮食的工作是未知的。这些研究的目的是确定生理
可以减缓或逆转CKD进程的机制。sKlotho通常由肾脏产生,
释放到循环中,保留肾功能,并预防许多肾移植的全身并发症。
失败随着肾脏疾病的进展,血清和尿液sKlotho水平下降,患者获得特征性
类似于Klotho-/-小鼠的过早衰老表型。肾脏是sKlotho的来源,
通过肾静脉中Klotho水平高的发现,双侧肾切除术降低了sKlotho,
肾特异性Klotho缺失具有与Klotho-/-在表型上不可区分疾病模式
小鼠sKlotho水平可能被调节的可能生理机制尚未确定。我们
发现,在完整的小鼠和大鼠,小鼠肾皮质匀浆,和培养的细胞,钙敏感
受体(CaSR)激活通过ADAM 10介导的脱落增加sKlotho水平。配体的能力
随着碱性pH环境的增加,以及酸性pH环境的改变,
降低CaSR信号传导。我们发现碱负荷增加了小鼠和大鼠中的CaSR信号传导和sKlotho,
碱性环境增加了小鼠肾匀浆和培养细胞中的Klotho脱落,
口服枸橼酸钾72小时增加人血清和尿Klotho
志愿者这些结果定义了一种新的生理机制,通过肾脏调节sKlotho水平。
我们假设酸中毒加速了肾功能的丧失,而碱化减慢了肾功能的丧失。
在CKD中发挥作用,因为酸中毒减少,碱性增加肾CaSR刺激的Klotho
从肾脏脱落该假设将通过以下研究得到发展:1)小鼠,CaSR-/-小鼠,肾
匀浆,培养的细胞,这将证明肾Klotho脱落是由CaSR调节,
对CaSR配体和pH的响应; 2)CKD疾病模型,以显示碱处理增加sKlotho水平
并减少肾损伤和心脏肥大,以及3)肾组织和培养细胞,以确定机制
允许CaSR、Klotho和ADAM 10相互作用,重点是C8四跨膜蛋白家族。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Richard Tyler Miller其他文献
Richard Tyler Miller的其他文献
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{{ truncateString('Richard Tyler Miller', 18)}}的其他基金
Physiologic regulation of soluble Klotho levels by systemic acid/base status
全身酸/碱状态对可溶性 Klotho 水平的生理调节
- 批准号:
9890373 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Physiologic regulation of soluble Klotho levels by systemic acid/base status
全身酸/碱状态对可溶性 Klotho 水平的生理调节
- 批准号:
10454775 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Novel Ca receptor signaling pathways for control of renal ion transport
控制肾离子转运的新型 Ca 受体信号通路
- 批准号:
8262613 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Novel Ca receptor signaling pathways for control of renal ion transport
控制肾离子转运的新型 Ca 受体信号通路
- 批准号:
7687870 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Novel Ca receptor signaling pathways for control of renal ion transport
控制肾离子转运的新型 Ca 受体信号通路
- 批准号:
8195579 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Novel Ca receptor signaling pathways for control of renal ion transport
控制肾离子转运的新型 Ca 受体信号通路
- 批准号:
7782797 - 财政年份:2009
- 资助金额:
-- - 项目类别:
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