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Isolation, Characterization, And High Throughput Extracellular Flux Analysis of Mouse Primary Renal Tubular Epithelial Cells
Published on: June 20, 2018
Albumin downregulates Klotho in tubular cells
Beatriz Fernandez-Fernandez1,2,3, M Concepcion Izquierdo1,2,3, Lara Valiño-Rivas1,2,3
1Department of Nephrology, IIS-Fundación Jiménez Díaz-Universidad Autónoma de Madrid, Madrid, Spain.
Insights
Albuminuria directly reduces Klotho protein in kidney tubular cells, contributing to cardiovascular aging in early chronic kidney disease (CKD). This finding explains Klotho deficiency in patients with normal kidney function but high albumin levels.
Area of Science:
- Nephrology
- Cardiovascular Aging
- Molecular Biology
Background:
- Kidney tubular cells produce Klotho, a protein crucial for regulating phosphate and preventing premature cardiovascular aging.
- Genetic Klotho deficiency in mice leads to accelerated cardiovascular aging.
- Acquired Klotho deficiency is a hallmark of human chronic kidney disease (CKD), even in early stages (G1 CKD) with normal glomerular filtration rate (GFR) and without significant uremic toxin buildup.
Purpose of the Study:
- To investigate if albuminuria, a marker for early CKD, directly diminishes Klotho expression.
- To explore this effect in human CKD patients, preclinical animal models, and cell cultures.
Main Methods:
- Correlated albuminuria with serum phosphate in a CKD cohort, adjusting for GFR, age, and sex.
- Induced proteinuria in rats and mice to assess kidney Klotho messenger ribonucleic acid (mRNA) and protein levels.
- Utilized Western blot and immunohistochemistry to quantify and localize Klotho expression in kidneys.
- Exposed cultured human and murine tubular cells to albumin and measured Klotho mRNA and protein changes.
- Investigated the role of histone deacetylase (HDAC) inhibition (trichostatin A) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibition.
Main Results:
- Albuminuria correlated with higher serum phosphate in CKD patients, independent of GFR.
- Urinary Klotho levels were reduced in patients with pathological albuminuria but preserved GFR.
- Proteinuric animal models showed interstitial inflammation and decreased kidney Klotho mRNA and protein, localized to tubular cells.
- In vitro, albumin directly reduced Klotho mRNA and protein expression in tubular cells.
- Albumin-induced Klotho downregulation was mitigated by HDAC inhibition but not NF-κB inhibition.
Conclusions:
- Albumin directly suppresses Klotho expression in kidney tubular cells.
- This mechanism likely contributes to Klotho deficiency observed in early CKD stages.
- The findings may explain fibroblast growth factor 23 (FGF23) resistance in proteinuric kidney disease.
Background:
Kidney tubular cells are the main sources of Klotho, a protein with phosphaturic action. Genetic Klotho deficiency causes premature cardiovascular aging in mice. Human chronic kidney disease (CKD) is characterized by acquired Klotho deficiency. Despite the lack of uremic toxin accumulation, Category G1 CKD [(normal glomerular filtration rate (GFR)] is already associated with decreased Klotho and with premature cardiovascular aging.
Methods:
We have explored whether albuminuria, a criterion to diagnose CKD when GFR is normal, may directly decrease Klotho expression in human CKD, preclinical models and cultured tubular cells.
Results:
In a CKD cohort, albuminuria correlated with serum phosphate after adjustment for GFR, age and sex. In this regard, urinary Klotho was decreased in patients with pathological albuminuria but preserved GFR. Proteinuria induced in rats by puromycin aminonucleoside and in mice by albumin overload was associated with interstitial inflammation and reduced total kidney Klotho messenger ribonucleic acid (mRNA) expression. Western blot disclosed reduced kidney Klotho protein in proteinuric rats and mice and immunohistochemistry localized the reduced kidney Klotho expression to tubular cells in proteinuric animals. In cultured murine and human tubular cells, albumin directly decreased Klotho mRNA and protein expression. This was inhibited by trichostatin A, an inhibitor of histone deacetylases, but unlike cytokine-induced Klotho downregulation, not by inhibitors of nuclear factor kappa-light-chain-enhancer of activated B cells.
Conclusions:
In conclusion, albumin directly decreases Klotho expression in cultured tubular cells. This may explain, or at least contribute to, the decrease in Klotho and promote fibroblast growth factor 23 resistance in early CKD categories, as observed in preclinical and clinical proteinuric kidney disease.
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