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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：
9890373
负责人：
Richard Tyler Miller
金额：
--
依托单位：
VA NORTH TEXAS HEALTH CARE SYSTEM
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：
https://reporter.nih.gov/project-details/9890373
关键词：
Acidosis Acids Adenine Alkalies Alkalinization American Animal Model Atrophic condition of skin Bicarbonates Bilateral Blood Blood Circulation Blood Vessels Calcium-Sensing Receptors Cells Characteristics Chemicals Chronic Chronic Kidney Failure Citrates Clinical Research Clinical Trials Contralateral Cultured Cells DASH diet Dialysis procedure Diet Disease Disease Progression Disease model Distal convoluted renal tubule structure Divalent Cations Early treatment Effectiveness of Interventions End stage renal failure Endothelin Environment Family GTP-Binding Protein alpha Subunits, Gs Goals Health Heart Hypertrophy Human Human Volunteers Hypertension Inflammation Injury to Kidney Ischemia Kidney Kidney Diseases Kidney Failure Knockout Mice Lead Ligands Link Measures Mediating Membrane Microdomains Metabolism Modeling Multiprotein Complexes Mus Nephrectomy Oral Parathyroid gland Pathway interactions Patients Pattern Phenotype Physiological Premature aging syndrome Production Proteins Public Health Rattus Receptor Activation Receptor Signaling Regulation Renal Tissue Renal function Renal tubule structure Renin-Angiotensin-Aldosterone System Reperfusion Therapy Scaffolding Protein Serum Small Interfering RNA Sodium Bicarbonate Source Specificity Structure of renal vein Supplementation System Testing Tissues Transplantation Urine Vascular Diseases Vascular calcification Veterans Work aged alkalinity base calcification coronary fibrosis disease phenotype endothelial dysfunction falls feeding functional loss in vivo kidney fibrosis knock-down loss of function mouse model novel preservation prevent receptor renal calcium response sarcopenia

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）经常发展为终末期肾脏疾病并伴有并发症