Elevated serum 1,25(OH)2-vitamin D3 level attenuates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction in kl/kl mice

Sun, Yujing; Zhou, Guangjun; Gui, Ting; Shimokado, Aiko; Nakanishi, Masayoshi; Oikawa, Kosuke; Sato, Fuyuki; Muragaki, Yasuteru

doi:10.1038/srep06563

Cited by 13 publications

(10 citation statements)

References 38 publications

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“…Moreover, we selected NRK52E cells which are representative and reliable for the investigation of TGF-β1-mediated fibrotic changes 56 . Activation of the TGF-β1-Smad3 pathway is observed during progression of fibrosis in UUO mice and NRK-52E cells, as reported by numerous studies 57 – 59 . Taken together, our data from UUO mice, rat kidney cells and human biopsy samples indicate that histone H3.3 and HIRA are implicated in TGF-β1-induced renal fibrosis.…”

Section: Discussionsupporting

confidence: 71%

TGF-β1 promotes expression of fibrosis-related genes through the induction of histone variant H3.3 and histone chaperone HIRA

Shindo

Doi

Nakashima

et al. 2018

Sci Rep

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Renal fibrosis is a histological manifestation that occurs in almost every type of chronic kidney disease. Histone variant H3.3 and its chaperone, histone cell cycle regulation defective homolog A (HIRA), serve as epigenetic marks that regulate transcriptional activity. In this study, we assessed the roles of histone H3.3 and HIRA in unilateral ureteral-obstruction (UUO) mice. In UUO mice, the levels of histone H3.3 and HIRA were significantly upregulated in the kidneys. These upregulated levels were decreased by a TGF-β1 neutralizing antibody. TGF-β1 induced histone H3.3 and HIRA expression in vitro via a Smad3-dependent pathway in normal rat kidney (NRK)−52E cells. Additionally, knockdown of HIRA expression decreased histone H3.3 expression and fibrogenesis in NRK-52E cells after TGF-β1 stimulation. Chromatin immunoprecipitation analysis revealed that promoters of fibrosis-related genes were immunoprecipitated with both histone H3.3 and HIRA in NRK-52E cells. Lastly, in human kidney biopsies from patients diagnosed with IgA nephropathy, histone H3.3 and HIRA immunostaining correlated positively with areas of fibrosis and estimated glomerular filtration rate. In conclusion, TGF-β1 induces expression of histone H3.3 and HIRA, which regulates expression of fibrosis-related genes.

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Section: Discussionsupporting

confidence: 71%

TGF-β1 promotes expression of fibrosis-related genes through the induction of histone variant H3.3 and histone chaperone HIRA

Shindo

Doi

Nakashima

et al. 2018

Sci Rep

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“…3C ). Furthermore, the a-SMA, collagen, type I, alpha 1 ( Col1a1 ), and connective tissue growth factor ( CTGF ) mRNA, which were markers for kidney fibrosis and downstream targets of TGF-β 26 27 , also exhibited significantly lower levels in FTO –/– kidneys after UUO ( Fig. 3D ).…”

Section: Resultsmentioning

confidence: 99%

FTO modulates fibrogenic responses in obstructive nephropathy

Wang

Shie

Tsai

et al. 2016

Sci Rep

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Genome-wide association studies have shown that variants in fat mass and obesity-associated (FTO) gene are robustly associated with body mass index and obesity. These FTO variants are also associated with end stage renal disease and all-cause mortality in chronic kidney diseases. However, the exact role of FTO in kidneys is currently unknown. Here we show that FTO expression is increased after ureteral obstruction and renal fibrosis. Deficiency of the FTO gene attenuates the fibrogenic responses induced by ureteral obstruction in the kidney. Renal tubular cells deficient of FTO produce less α-SMA after TGF-β stimulation. FTO is indispensable for the extracellular matrix synthesis after ureteral obstruction in kidneys. Indeed, global gene transcriptions amplitude is reduced in FTO deficient kidneys after ureteral obstruction. These data establish the importance of FTO in renal fibrosis, which may have potential therapeutic implications.

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“…Lower Ca levels were seen in Pin1 KO mice after HPD ( Fig 2B ) without significant change in potassium levels ( Fig 2C ). On the other hand, Pin1 deficiency was associated with increased serum vitamin D regardless of HPD ( Fig 2D ), which may contribute to the decreased fibrotic phenotype observed in KO mice [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

Phosphate–Induced Renal Fibrosis Requires the Prolyl Isomerase Pin1

Shiizaki

Kuro‐o

et al. 2016

PLoS ONE

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Tubulo-interstitial fibrosis is a common, destructive endpoint for a variety of kidney diseases. Fibrosis is well correlated with the loss of kidney function in both humans and rodents. The identification of modulators of fibrosis could provide novel therapeutic approaches to reducing disease progression or severity. Here, we show that the peptidyl-prolyl isomerase Pin1 is an important molecular contributor that facilitates renal fibrosis in a well-characterized animal model. While wild-type mice fed a high phosphate diet (HPD) for 8–12 weeks developed calcium deposition, macrophage infiltration and extracellular matrix (ECM) accumulation in the kidney interstitium, Pin1 null mice showed significantly less pathology. The serum Pi in both WT and KO mice were significantly increased by the HPD, but the serum Ca was slightly decreased in KO compared to WT. In addition, both WT and KO HPD mice had less weight gain but exhibited normal organ mass (kidney, lung, spleen, liver and heart). Unexpectedly, renal function was not initially impaired in either genotype irrespective of the HPD. Our results suggest that diet containing high Pi induces rapid renal fibrosis before a significant impact on renal function and that Pin1 plays an important role in the fibrotic process.

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Elevated serum 1,25(OH)2-vitamin D3 level attenuates renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction in kl/kl mice

Cited by 13 publications

References 38 publications

TGF-β1 promotes expression of fibrosis-related genes through the induction of histone variant H3.3 and histone chaperone HIRA

TGF-β1 promotes expression of fibrosis-related genes through the induction of histone variant H3.3 and histone chaperone HIRA

FTO modulates fibrogenic responses in obstructive nephropathy

Phosphate–Induced Renal Fibrosis Requires the Prolyl Isomerase Pin1

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