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1.
Am J Physiol Lung Cell Mol Physiol ; 321(4): L736-L749, 2021 10 01.
Article in English | MEDLINE | ID: mdl-34346778

ABSTRACT

Normal lungs do not express α-Klotho (Klotho) protein but derive cytoprotection from circulating soluble Klotho. It is unclear whether chronic supranormal Klotho levels confer additional benefit. To address this, we tested the age-related effects of modest Klotho overexpression on acute lung injury (ALI) and recovery. Transgenic Klotho-overexpressing (Tg-Kl) and wild-type (WT) mice (2 and 6 mo old) were exposed to hyperoxia (95% O2; 72 h; injury; Hx) then returned to normoxia (21% O2; 24 h; recovery; Hx-R). Control mice were kept in normoxia. Renal and serum Klotho, lung histology, and bronchoalveolar lavage fluid oxidative damage markers were assessed. Effects of hyperoxia on Klotho release were tested in human embryonic kidney cells stably expressing Klotho. A549 lung epithelial cells transfected with Klotho cDNA or vector were exposed to cigarette smoke; lactate dehydrogenase and double-strand DNA breaks were measured. Serum Klotho decreased with age. Hyperoxia suppressed renal Klotho at both ages and serum Klotho at 2 mo of age. Tg-Kl mice at both ages and 2-mo-old WT mice survived Hx-R; 6-mo-old Tg-Kl mice showed lower lung damage than age-matched WT mice. Hyperoxia directly inhibited Klotho expression and release in vitro; Klotho transfection attenuated cigarette smoke-induced cytotoxicity and DNA double-strand breaks in lung epithelial cells. Young animals with chronic high baseline Klotho expression were more resistant to ALI. Chronic constitutive Klotho overexpression in older Tg-Kl animals attenuated hyperoxia-induced lung damage and improves survival and short-term recovery despite an acute reduction in serum Klotho during injury. We conclude that chronic enhancement of Klotho expression increases resilience to ALI.


Subject(s)
Acute Lung Injury/prevention & control , Glucuronidase/blood , Glucuronidase/metabolism , Smoke/adverse effects , Acute Lung Injury/pathology , Animals , Cell Line , Cytoprotection/genetics , Cytoprotection/physiology , DNA Breaks, Double-Stranded , DNA Damage/genetics , Female , Glucuronidase/genetics , HEK293 Cells , Humans , Hyperoxia , Klotho Proteins , L-Lactate Dehydrogenase/analysis , Lung/metabolism , Male , Mice , Mice, Transgenic
2.
Clin J Am Soc Nephrol ; 14(3): 411-420, 2019 03 07.
Article in English | MEDLINE | ID: mdl-30745301

ABSTRACT

BACKGROUND AND OBJECTIVES: Idiopathic uric acid nephrolithiasis, which is closely associated with obesity and the metabolic syndrome, is increasing in prevalence. Unduly acidic urine pH, the quintessential pathophysiologic feature of this disease, is in part explained by inadequate excretion of the principal urinary buffer ammonium. The role of net acid excretion in the pathogenesis of uric acid nephrolithiasis is incompletely understood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We compared acid-base parameters of patients with idiopathic uric acid nephrolithiasis with matched control subjects under controlled diets in an inpatient metabolic unit. Measurements included fasting blood and 24-hour urine chemistries and 24-hour urine metabolomic analysis. Comparisons between groups included analysis of covariance models controlling for urine pH or body mass index. RESULTS: Subjects with idiopathic uric acid nephrolithiasis had lower urine pH (5.5 versus 5.9; P<0.001) and higher net acid excretion (60 versus 43 mEq/24 h; P<0.001), with the excess H+ carried by nonammonium buffers. In all subjects, there was a positive relationship of net acid excretion with higher body mass index in spite of strictly controlled equivalent dietary acid intake. This relationship was most evident among control subjects (r=0.36; P=0.03). It was attenuated in patients with idiopathic uric acid nephrolithiasis whose net acid excretion remained fixedly high and ammonium excretion remained low relative to net acid excretion, resulting in low urine pH over a wide body mass index range. Urinary metabolomics was performed to attempt to identify excess organic acids presented to the kidney in idiopathic uric acid nephrolithiasis. Among the tricarboxylic acid cycle intermediates and amino acid and lipid metabolites analyzed, 26 organic anions with acid dissociation constants values in the range of urine pH showed greater protonation. However, protons carried by the identified organic acids did not entirely account for the higher titratable acidity seen in idiopathic uric acid nephrolithiasis. CONCLUSIONS: Higher acid load to the kidney, resulting in higher urinary net acid excretion, is an important factor in the pathogenesis of idiopathic uric acid nephrolithiasis.


Subject(s)
Acid-Base Equilibrium , Kidney/physiopathology , Nephrolithiasis/physiopathology , Renal Elimination , Uric Acid/urine , Biomarkers/urine , Body Mass Index , Case-Control Studies , Diet/adverse effects , Female , Humans , Hydrogen-Ion Concentration , Male , Middle Aged , Nephrolithiasis/diagnosis , Nephrolithiasis/etiology , Nephrolithiasis/urine , Pilot Projects , Risk Factors
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