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Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2021 Aug 16; Vol. 131 (16). - Publication Year :
- 2021
-
Abstract
- The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.
- Subjects :
- Animals
Body Fluids chemistry
Calcium Phosphates chemistry
Cell Line
Crystallization
Diet, Western adverse effects
Disease Progression
Endocytosis
Fibroblast Growth Factor-23
Fibroblast Growth Factors blood
Homeostasis
Humans
Kidney Tubules pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphates administration & dosage
Phosphates adverse effects
Renal Insufficiency, Chronic etiology
Renal Insufficiency, Chronic pathology
Toll-Like Receptor 4 deficiency
Toll-Like Receptor 4 genetics
Toll-Like Receptor 4 metabolism
Calcium Phosphates metabolism
Kidney Tubules metabolism
Renal Insufficiency, Chronic metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 131
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 34185705
- Full Text :
- https://doi.org/10.1172/JCI145693