Effects of orally active hypoxia inducible factor alpha prolyl hydroxylase inhibitor, FG4592 on renal fibrogenic potential in mouse unilateral ureteral obstruction model

Kabei, Kazuya; Yu, Tao; Shiota, Masayuki; Osada‐Oka, Mayuko; Nishide, Shunji; Uchida, Junji; Nakatani, Tatsuya; Matsunaga, Satoru; Yamaguchi, Takehiro; Tomita, Shuhei; Miura, Katsuyuki

doi:10.1016/j.jphs.2019.12.002

Cited by 26 publications

(18 citation statements)

References 25 publications

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“…Treatment in rodent models of CKD with other HIF-PHI, such as Roxadustat and Enardodustat, showed improvements in markers of kidney fibrosis and inflammation, although this is not associated with FGF23. (57,58) Although the fibrosis marker genes Col1a1 and Col3a1 mRNAs were reduced, we did not observe improvements in kidney fibrosis as assessed by histology in our study. It is likely that our model had established renal fibrosis that would be difficult to prevent or reverse over a 3-week treatment period, and the downregulation of renal fibrosis makers was potentially not enough of a compensation to overcome fibrotic damage.…”

Section: Discussioncontrasting

confidence: 86%

The HIF-PHI BAY 85-3934 (Molidustat) Improves Anemia and Is Associated With Reduced Levels of Circulating FGF23 in a CKD Mouse Model

Noonan

Agoro

et al. 2020

Journal of Bone and Mineral Research

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Fibroblast growth factor‐23 (FGF23) is a critical factor in chronic kidney disease (CKD), with elevated levels causing alterations in mineral metabolism and increased odds for mortality. Patients with CKD develop anemia as the kidneys progressively lose the ability to produce erythropoietin (EPO). Anemia is a potent driver of FGF23 secretion; therefore, a hypoxia‐inducible factor prolyl hydroxylase inhibitor (HIF‐PHI) currently in clinical trials to elevate endogenous EPO to resolve anemia was tested for effects on iron utilization and FGF23‐related parameters in a CKD mouse model. Mice were fed either a casein control diet or an adenine‐containing diet to induce CKD. The CKD mice had markedly elevated iFGF23 and blood urea nitrogen (BUN), hyperphosphatemia, and anemia. Cohorts of mice were then treated with a patient‐equivalent dose of BAY 85‐3934 (BAY; Molidustat), which elevated EPO and completely resolved aberrant complete blood counts (CBCs) in the CKD mice. iFGF23 was elevated in vehicle‐treated CKD mice (120‐fold), whereas circulating iFGF23 was significantly attenuated (>60%) in the BAY‐treated CKD mice. The BAY‐treated mice with CKD also had reduced BUN, but there was no effect on renal vitamin D metabolic enzyme expression. Consistent with increased EPO, bone marrow Erfe, Transferrin receptor (Tfrc), and EpoR mRNAs were increased in BAY‐treated CKD mice, and in vitro hypoxic marrow cultures increased FGF23 with direct EPO treatment. Liver Bmp‐6 and hepcidin expression were downregulated in all BAY‐treated groups. Femur trabecular parameters and cortical porosity were not worsened with BAY administration. In vitro, differentiated osteocyte‐like cells exposed to an iron chelator to simulate iron depletion/hypoxia increased FGF23; repletion with holo‐transferrin completely suppressed FGF23 and normalized Tfrc1. Collectively, these results support that resolving anemia using a HIF‐PHI during CKD was associated with lower BUN and reduced FGF23, potentially through direct restoration of iron utilization, thus providing modifiable outcomes beyond improving anemia for this patient population. © 2021 American Society for Bone and Mineral Research (ASBMR).

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Section: Discussioncontrasting

confidence: 86%

The HIF-PHI BAY 85-3934 (Molidustat) Improves Anemia and Is Associated With Reduced Levels of Circulating FGF23 in a CKD Mouse Model

Noonan

Agoro

et al. 2020

Journal of Bone and Mineral Research

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“…Finally, it is worth mentioning that a recently published paper demonstrated that FG4592 had little effect on unilateral ureteral obstruction (UUO)-induced renal fibrosis (41) and our team has confirmed this result (data not shown). In contrast to…”

Section: Hif-1 Is Activated In Uir Mice Kidney and Human Fibrotic Kidneyssupporting

confidence: 66%

Anti-anemia drug FG4592 retards the AKI-to-CKD transition by improving vascular regeneration and antioxidative capability

Chen

Miao

et al. 2021

Clinical Science

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Acute kidney injury (AKI) is a known risk factor for the development of chronic kidney disease (CKD), with no satisfactory strategy to prevent the progression of AKI to CKD. Damage to the renal vascular system and subsequent hypoxia are common contributors to both AKI and CKD. Hypoxia inducible factor (HIF) is reported to protect the kidney from acute ischemic damage and a novel HIF stabilizer, FG4592 (Roxadustat), has become available in the clinic as an anti-anemia drug. However, the role of FG4592 in the AKI-to-CKD transition remains elusive. In the present study, we investigated the role of FG4592 in the AKI-to-CKD transition induced by unilateral kidney ischemia-reperfusion (UIR). The results showed that FG4592, given to mice 3 days after UIR, markedly alleviated kidney fibrosis and enhanced renal vascular regeneration, possibly via activating the HIF-1α/vascular endothelial growth factor A (VEGFA)/VEGF receptor 1 (VEGFR1) signaling pathway and driving the expression of the endogenous antioxidant superoxide dismutase 2 (SOD2). In accordance with the improved renal vascular regeneration and redox balance, the metabolic disorders of the UIR mice kidneys were also attenuated by treatment with FG4592. However, the inflammatory response in the UIR kidneys was not affected significantly by FG-4592. Importantly, in the kidneys of CKD patients, we also observed enhanced HIF-1α expression which was positively correlated with the renal levels of VEGFA and SOD2. Together, these findings demonstrated the therapeutic effect of the anti-anemia drug FG-4592 in preventing the AKI-to-CKD transition related to ischemia and the redox imbalance.

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“…The action mechanism of PHI is through avoiding HIF proteasomal degradation as an acute protective response [ 99 , 100 , 101 ]; however, although it was not demonstrated, possible inhibition of collagen synthesis could also contribute to PHI benefits in kidney diseases. Since HIF is necessary for erythropoiesis induction, PHI roxadustat and GSK1278863 also has been proposed for anemia treatment in CKD, demonstrating the increase in erythropoietin and hematocrit levels in animal models [ 103 , 104 ] and even in patients [ 105 ]; hence in CKD and AKI, there is an increase in PHD activity, and their inhibition ameliorates damage associated with kidney dysfunction.…”

Section: Alpha-ketoglutaratementioning

confidence: 99%

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

et al. 2021

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Mitochondria are complex organelles that orchestrate several functions in the cell. The primary function recognized is energy production; however, other functions involve the communication with the rest of the cell through reactive oxygen species (ROS), calcium influx, mitochondrial DNA (mtDNA), adenosine triphosphate (ATP) levels, cytochrome c release, and also through tricarboxylic acid (TCA) metabolites. Kidney function highly depends on mitochondria; hence mitochondrial dysfunction is associated with kidney diseases. In addition to oxidative phosphorylation impairment, other mitochondrial abnormalities have been described in kidney diseases, such as induction of mitophagy, intrinsic pathway of apoptosis, and releasing molecules to communicate to the rest of the cell. The TCA cycle is a metabolic pathway whose primary function is to generate electrons to feed the electron transport system (ETS) to drives energy production. However, TCA cycle metabolites can also release from mitochondria or produced in the cytosol to exert different functions and modify cell behavior. Here we review the involvement of some of the functions of TCA metabolites in kidney diseases.

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Effects of orally active hypoxia inducible factor alpha prolyl hydroxylase inhibitor, FG4592 on renal fibrogenic potential in mouse unilateral ureteral obstruction model

Cited by 26 publications

References 25 publications

The HIF-PHI BAY 85-3934 (Molidustat) Improves Anemia and Is Associated With Reduced Levels of Circulating FGF23 in a CKD Mouse Model

The HIF-PHI BAY 85-3934 (Molidustat) Improves Anemia and Is Associated With Reduced Levels of Circulating FGF23 in a CKD Mouse Model

Anti-anemia drug FG4592 retards the AKI-to-CKD transition by improving vascular regeneration and antioxidative capability

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

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