Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression
Kazuhiro Shiizaki, … , Masayuki Murata, Makoto Kuro-o
Kazuhiro Shiizaki, … , Masayuki Murata, Makoto Kuro-o
Published June 29, 2021
Citation Information: J Clin Invest. 2021;131(16):e145693. https://doi.org/10.1172/JCI145693.
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Research Article Nephrology

Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression

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.

Authors

Kazuhiro Shiizaki, Asako Tsubouchi, Yutaka Miura, Kinya Seo, Takahiro Kuchimaru, Hirosaka Hayashi, Yoshitaka Iwazu, Marina Miura, Batpurev Battulga, Nobuhiko Ohno, Toru Hara, Rina Kunishige, Mamiko Masutani, Keita Negishi, Kazuomi Kario, Kazuhiko Kotani, Toshiyuki Yamada, Daisuke Nagata, Issei Komuro, Hiroshi Itoh, Hiroshi Kurosu, Masayuki Murata, Makoto Kuro-o

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Figure 3

TLR4 expressed in renal tubules is required for a high-phosphate diet to induce kidney damage.

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TLR4 expressed in renal tubules is required for a high-phosphate diet to...
Mice lacking the Tlr4 gene in renal tubular cells (Tlr4-Cre) and control Cre mice (mice carrying the Cre transgene alone) at 4 weeks of age were placed on a high-phosphate diet containing 2.0% inorganic phosphate (HP) for 4 weeks. Relative renal mRNA levels of the markers for tubule damage and inflammation (A) and fibrosis (B) were determined by quantitative RT-PCR. (C) No difference was detected in the amount of urinary phosphate excretion between Tlr4-Cre mice (n = 13) and Cre mice (n = 9). (D–F) Picrosirius red staining of the kidney sections detected patchy red areas of interstitial fibrosis in the cortex and the cortico-medullary junction (CMJ) in the control mice (HP, Cre) but not in the mice lacking the Tlr4 gene in renal tubular cells (HP, Tlr4-Cre). Scale bars: 100 μm. (G) The fibrotic area was quantified in the cortex (upper panel) and the CMJ (lower panel) in the individual mice (n = 4 mice per group). Data are indicated as the mean ± SD. **P < 0.01 versus Cre mice, by Mann-Whitney U test (A and B); **P < 0.01, by 1-way ANOVA with Tukey’s multiple-comparison test (G).