Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes

Nabeshima, Yoko; Washida, Miwa; Tamura, Masahito; Maeno, Akiteru; Ohnishi, Mutsuko; Shiroishi, Toshihiko; Imura, Akihiro; Razzaque, Mohammed S.; Nabeshima, Yo‐ichi

doi:10.1038/srep05847

Cited by 23 publications

(22 citation statements)

References 52 publications

(87 reference statements)

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“…Calpains are considered potential therapeutic targets in Alzheimer’s disease [44], aging [45], and diabetes [46]. Calpains regulate the functions of many proteins, thereby modulating multiple physiological processes including apoptosis, cytoskeletal reorganization, and hemostasis [14, 47].…”

Section: Discussionmentioning

confidence: 99%

Calpain-1 regulates platelet function in a humanized mouse model of sickle cell disease

Nwankwo

Gremmel

Gerrits

et al. 2017

Thrombosis Research

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One of the major contributors to sickle cell disease (SCD) pathobiology is the hemolysis of sickle red blood cells (RBCs), which release free hemoglobin and platelet agonists including adenosine 5’-diphosphate (ADP) into the plasma. While platelet activation/aggregation may promote tissue ischemia and pulmonary hypertension in SCD, modulation of sickle platelet dysfunction remains poorly understood. Calpain-1, a ubiquitous calcium-activated cysteine protease expressed in the hematopoietic cells, mediates aggregation of platelets in healthy mice. We generated calpain-1 knockout Townes sickle (SSCKO) mice to investigate the role of calpain-1 in the steady state and hypoxia/reoxygenation (H/R)-induced sickle platelet activation and aggregation, clot retraction, and pulmonary arterial hypertension. Using multi-electrode aggregometry, which measures platelet adhesion and aggregation in whole blood, we determined that steady state SSCKO mice exhibit significantly impaired PAR4-TRAP-stimulated platelet aggregation as compared to Townes sickle (SS) and humanized control (AA) mice. Interestingly, the H/R injury induced platelet hyperactivity in SS and SSCKO, but not AA mice, partially rescued the aggregation defect in SSCKO mice. The PAR4-TRAP-stimulated GPIIb-IIIa/αIIbβ3 integrin activation was normal in SSCKO platelets suggesting that an alternate mechanism mediates the impaired platelet aggregation in steady state SSCKO mice. Taken together, we provide the first evidence that calpain-1 regulates platelet hyperactivity in sickle mice, and may offer a viable pharmacological target to reduce platelet hyperactivity in SCD.

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Section: Discussionmentioning

confidence: 99%

Calpain-1 regulates platelet function in a humanized mouse model of sickle cell disease

Nwankwo

Gremmel

Gerrits

et al. 2017

Thrombosis Research

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“…In conclusion, we herein propose a previously unrecognized function for extracellular Pi in the regulation of the aging process. Because the blockade of calpain 1 or a plasminogen activator inhibitor-1 deficiency in Kl 2/2 mice is known to extend longevity, 39,40 further analyses are warranted to determine the importance of the proposed pathway in this context. Our results are clinically important because they provide a were plotted.…”

Section: Discussionmentioning

confidence: 99%

Inorganic Phosphate Activates the AKT/mTORC1 Pathway and Shortens the Life Span of an α‑Klotho–Deficient Model

Kawai

Kinoshita

Ozono

et al. 2016

JASN

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Inorganic phosphate (Pi) has been implicated in the pathogenesis of accelerated aging; however, the underlying mechanisms remain elusive. Herein, we demonstrated in cultured cells and in vivo that increased levels of extracellular Pi activated the AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway by suppressing membrane-bound phosphatase and tensin homolog (PTEN) levels in a manner requiring the sodium-dependent Pi transporter PiT-1. High levels of extracellular Pi also led to phosphorylation of Ser/Thr clusters in the C-terminal tail of PTEN, which has been shown to dissociate PTEN from the membrane. Notably, blockade of mTORC1 activity by rapamycin treatment prolonged the life span of hyperphosphatemic a-Klotho-deficient (Kl 2/2 ) mice. Dietary correction of hyperphosphatemia or treatment with rapamycin also rescued the brown adipose tissue dysfunction and oxidative damage observed in Kl 2/2 mice. Furthermore, rapamycin treatment partially rescued these effects and extended the life span when Kl 2/2 mice were maintained on a high-phosphate diet. Finally, rapamycin reduced circulating Pi levels in Kl 2/2 mice, apparently by decreasing the localization of sodium-dependent Pi transport protein 2a at the renal brush border membrane. Therefore, the activation of mTORC1 may create a vicious loop that exacerbates the retention of Pi, which in turn may enhance oxidative damage and ultimately shorten the life span of Kl 2/2 mice. These results demonstrate that Pi has important roles in the aging process, and the blockade of mTORC1 may have therapeutic potential for premature aging-like symptoms associated with hyperphosphatemia.

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“…41 Genetically altered alpha-klotho-knockout mice develop phosphate toxicity as early as at 3 weeks of age, which affects weight gain and the bone maturation process, produces a generalized soft tissue atrophy and results in reduced life span. 1,14,[40][41][42][43][44][45][46] In vivo studies found that phosphate toxicity in alpha-klotho ablated mice is associated with increased renal activity of NaPi2a. However, phosphate Phosphate toxicity RB Brown et al burden was lowered in hyperphosphatemic alpha-klothoknockout mice by generating NaPi2a/alpha-klotho doubleknockout mice, which resulted in prolonged survival.…”

Section: Phosphate Toxicitymentioning

confidence: 99%

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity

Brown

2015

BoneKEy Reports

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Phosphate homeostasis is coordinated and regulated by complex cross-organ talk through delicate hormonal networks. Parathyroid hormone (PTH), secreted in response to low serum calcium, has an important role in maintaining phosphate homeostasis by influencing renal synthesis of 1,25-dihydroxyvitamin D, thereby increasing intestinal phosphate absorption. Moreover, PTH can increase phosphate efflux from bone and contribute to renal phosphate homeostasis through phosphaturic effects. In addition, PTH can induce skeletal synthesis of another potent phosphaturic hormone, fibroblast growth factor 23 (FGF23), which is able to inhibit renal tubular phosphate reabsorption, thereby increasing urinary phosphate excretion. FGF23 can also fine-tune vitamin D homeostasis by suppressing renal expression of 1-alpha hydroxylase (1a(OH)ase). This review briefly discusses how FGF23, by forming a bone-kidney axis, regulates phosphate homeostasis, and how its dysregulation can lead to phosphate toxicity that induces widespread tissue injury. We also provide evidence to explain how phosphate toxicity related to dietary phosphorus overload may facilitate incidence of noncommunicable diseases including kidney disease, cardiovascular disease, cancers and skeletal disorders.

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Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes

Cited by 23 publications

References 52 publications

Calpain-1 regulates platelet function in a humanized mouse model of sickle cell disease

Calpain-1 regulates platelet function in a humanized mouse model of sickle cell disease

Inorganic Phosphate Activates the AKT/mTORC1 Pathway and Shortens the Life Span of an α‑Klotho–Deficient Model

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity

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