AKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus

Ando, Fumiaki; Mori, Shigeo; Yui, Naofumi; Morimoto, Takeshi; Nomura, Naohiro; Sohara, Eisei; Rai, Tatemitsu; Sasaki, Sei; Kondo, Yoshiaki; Kagechika, Hiroyuki; Uchida, Shinichi

doi:10.1038/s41467-018-03771-2

Cited by 39 publications

(32 citation statements)

References 46 publications

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“…We measured CK2 activity indirectly by using an antibody against the phospho-CK2 substrate (motif pS/pTDXE) to measure the amount of phosphorylated CK2 substrates. This method is widely used in literature to measure kinase activity, such as activity of the following kinases CK2 [ 16 , 49 , 50 , 51 , 52 ], AMPK [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ], AMT/ATR [ 64 , 65 , 66 , 67 , 68 , 69 , 70 ], PKA [ 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ], and PKC [ 77 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. Both CK2 knockdown and CX-4945 treatment inhibited the proliferation of CCA cells.…”

Section: Discussionmentioning

confidence: 99%

CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism

Lertsuwan

Sawasdichai

et al. 2018

Cancers

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Cholangiocarcinoma is a disease with a poor prognosis and increasing incidence and hence there is a pressing unmet clinical need for new adjuvant treatments. Protein kinase CK2 (previously casein kinase II) is a ubiquitously expressed protein kinase that is up-regulated in multiple cancer cell types. The inhibition of CK2 activity using CX-4945 (Silmitasertib) has been proposed as a novel treatment in multiple disease settings including cholangiocarcinoma. Here, we show that CX-4945 inhibited the proliferation of cholangiocarcinoma cell lines in vitro. Moreover, CX-4945 treatment induced the formation of cytosolic vacuoles in cholangiocarcinoma cell lines and other cancer cell lines. The vacuoles contained extracellular fluid and had neutral pH, features characteristic of methuosis. In contrast, simultaneous knockdown of both the α and α′ catalytic subunits of protein kinase CK2 using small interfering RNA (siRNA) had little or no effect on the proliferation of cholangiocarcinoma cell lines and failed to induce the vacuole formation. Surprisingly, low doses of CX-4945 increased the invasive properties of cholangiocarcinoma cells due to an upregulation of matrix metallopeptidase 7 (MMP-7), while the knockdown of CK2 inhibited cell invasion. Our data suggest that CX-4945 inhibits cell proliferation and induces cell death via CK2-independent pathways. Moreover, the increase in cell invasion brought about by CX-4945 treatment suggests that this drug might increase tumor invasion in clinical settings.

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Section: Discussionmentioning

confidence: 99%

CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism

Lertsuwan

Sawasdichai

et al. 2018

Cancers

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“…One that has now entered the clinical arena is the anti-FGF23 antibody burosumab in X-linked hypophosphatemic rickets (67). Another example is the recognition of the central role of cyclic AMP in kidney water handling, which has spurned investigations into novel treatments for nephrogenic diabetes that enhance AQP2 expression in the apical membrane independent of AVPR2 receptor activation (68)(69)(70).…”

Section: Translation Of Genetic Insightsmentioning

confidence: 99%

Inherited Tubulopathies of the Kidney

Downie

Lopez-Garcia

Kleta

et al. 2020

CJASN

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The kidney tubules provide homeostasis by maintaining the external milieu that is critical for proper cellular function. Without homeostasis, there would be no heartbeat, no muscle movement, no thought, sensation, or emotion. The task is achieved by an orchestra of proteins, directly or indirectly involved in the tubular transport of water and solutes. Inherited tubulopathies are characterized by impaired function of one or more of these specific transport molecules. The clinical consequences can range from isolated alterations in the concentration of specific solutes in blood or urine to serious and life-threatening disorders of homeostasis. In this review, we will focus on genetic aspects of the tubulopathies and how genetic investigations and kidney physiology have crossfertilized each other and facilitated the identification of these disorders and their molecular basis. In turn, clinical investigations of genetically defined patients have shaped our understanding of kidney physiology.

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“…Regulation of AQP2 by vasopressin is a result of vasopressin V2 receptor activation which triggers cyclic AMP‐dependent activation of a protein kinase network that causes increased transcription of AQP2, changes in its phosphorylation status, and redistribution of AQP2 to the luminal membrane (Knepper et al, ). The vasopressin‐induced increases in AQP2 phosphorylation at Ser269 has been proposed to be a more effective indicator of vasopressin activity than phosphorylation at Ser256 (Ando et al, ; Xie et al, ). In the current study, ipragliflozin increased vasopressin levels, the renal expression of the V2 vasopressn receptor, the phosphorylation of AQP2 at Ser269, and solute‐free water reabsorption, consistent with the notion that iplagliflozin‐stimulated vasopressin release increased free water reabsorption, at least in part, by AQP2 phosphorylation at Ser269.…”

Section: Discussionmentioning

confidence: 99%

Osmotic diuresis by SGLT2 inhibition stimulates vasopressin‐induced water reabsorption to maintain body fluid volume

et al. 2020

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Most of the filtered glucose is reabsorbed in the early proximal tubule by the sodium-glucose cotransporter SGLT2. The glycosuric effect of the SGLT2 inhibitor ipragliflozin is linked to a diuretic and natriuretic effect that activates compensatory increases in fluid and food intake to stabilize body fluid volume (BFV). However, the compensatory mechanisms that are activated on the level of renal tubules remain unclear. Type 2 diabetic Goto-Kakizaki (GK) rats were treated with vehicle or 0.01% (in diet) ipragliflozin with free access to fluid and food. After 8 weeks, GK rats were placed in metabolic cages for 24-hr. Ipragliflozin decreased body weight, serum glucose and systolic blood pressure, and increased fluid and food intake, urinary glucose and Na + excretion, urine volume, and renal osmolar clearance, as well as urine vasopressin and solute-free water reabsorption (TcH2O). BFV, measured by bioimpedance spectroscopy, and fluid balance were similar among the two groups. Urine vasopressin in ipragliflozin-treated rats was negatively and positively associated with fluid balance and TcH2O, respectively. Ipragliflozin increased the renal membrane protein expression of SGLT2, aquaporin (AQP) 2 phosphorylated at Ser269 and vasopressin V2 receptor. The expression of SGLT1, GLUT2, AQP1, and AQP2 was similar between the groups. In conclusion, the SGLT2 inhibitor ipragliflozin induced a sustained glucosuria, diuresis, and natriuresis, with compensatory increases in fluid intake and vasopressin-induced TcH2O in proportion to the reduced fluid balance to maintain BFV. These results indicate that the osmotic diuresis induced by SGLT2 inhibition stimulates compensatory fluid intake and renal water reabsorption to maintain BFV. K E Y W O R D Sbioimpedance analysis, glucosuria, SGLT2 inhibition, vasopressin, water reabsorption

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AKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus

Cited by 39 publications

References 46 publications

CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism

CX-4945 Induces Methuosis in Cholangiocarcinoma Cell Lines by a CK2-Independent Mechanism

Inherited Tubulopathies of the Kidney

Osmotic diuresis by SGLT2 inhibition stimulates vasopressin‐induced water reabsorption to maintain body fluid volume

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