Dataset Information

The Triad Na⁺ Activated Na⁺ Channel (Nax)-Salt Inducible KINASE (SIK) and (Na⁺ + K⁺)-ATPase: Targeting the Villains to Treat Salt Resistant and Sensitive Hypertension.

ABSTRACT: The Na⁺-activated Na⁺ channel (Nax) and salt-inducible kinase (SIK) are stimulated by increases in local Na⁺ concentration, affecting (Na⁺ + K⁺)-ATPase activity. To test the hypothesis that the triad Nax/SIK/(Na⁺ + K⁺)-ATPase contributes to kidney injury and salt-sensitive hypertension (HTN), uninephrectomized male Wistar rats (200 g; n = 20) were randomly divided into 4 groups based on a salt diet (normal salt diet; NSD-0.5% NaCl-or high-salt diet; HSD-4% NaCl) and subcutaneous administration of saline (0.9% NaCl) or deoxycorticosterone acetate (DOCA, 8 mg/kg), as follows: Control (CTRL), CTRL-Salt, DOCA, and DOCA-Salt, respectively. After 28 days, the following were measured: kidney function, blood pressure, (Na⁺ + K⁺)-ATPase and SIK1 kidney activities, and Nax and SIK1 renal expression levels. SIK isoforms in kidneys of CTRL rats were present in the glomerulus and tubular epithelia; they were not altered by HSD and/or HTN. CTRL-Salt rats remained normotensive but presented slight kidney function decay. HSD rats displayed augmentation of the Nax/SIK/(Na⁺ + K⁺)-ATPase pathway. HTN, kidney injury, and kidney function decay were present in all DOCA rats; these were aggravated by HSD. DOCA rats presented unaltered (Na⁺ + K⁺)-ATPase activity, diminished total SIK activity, and augmented SIK1 and Nax content in the kidney cortex. DOCA-Salt rats expressed SIK1 activity and downregulation in (Na⁺ + K⁺)-ATPase activity in the kidney cortex despite augmented Nax content. The data of this study indicate that the (Na⁺ + K⁺)-ATPase activity response to SIK is attenuated in rats under HSD, independent of HTN, as a mechanism contributing to kidney injury and salt-sensitive HTN.

SUBMITTER: Gonsalez SR

PROVIDER: S-EPMC10178781 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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The Triad Na+ Activated Na+ Channel (Nax)-Salt Inducible KINASE (SIK) and (Na+ + K+)-ATPase: Targeting the Villains to Treat Salt Resistant and Sensitive Hypertension.

Gonsalez Sabrina R SR Gomes Dayene S DS de Souza Alessandro M AM Ferrão Fernanda M FM Vallotton Zoe Z Gogulamudi Venkateswara R VR Lowe Jennifer J Casarini Dulce E DE Prieto Minolfa C MC Lara Lucienne S LS

International journal of molecular sciences 20230426 9

The Na+-activated Na+ channel (Nax) and salt-inducible kinase (SIK) are stimulated by increases in local Na+ concentration, affecting (Na+ + K+)-ATPase activity. To test the hypothesis that the triad Nax/SIK/(Na+ + K+)-ATPase contributes to kidney injury and salt-sensitive hypertension (HTN), uninephrectomized male Wistar rats (200 g; n = 20) were randomly divided into 4 groups based on a salt diet (normal salt d ...[more]

PMID: 37175599

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Project description:Osteoclasts are large multinucleated cells responsible for bone resorption. Excessive inflammatory activation of osteoclasts leads to bony erosions, which are the hallmark of several diseases such as rheumatoid arthritis (RA). Salt-inducible kinases (SIK) constitute a subfamily of kinases comprising three members (SIK1, -2, and -3). Inhibition of SIK kinase activity induces an anti-inflammatory phenotype in macrophages. Since osteoclasts originate from precursors of macrophage origin, we hypothesized a role of SIK in osteoclastogenesis. We analyzed SIK1, -2 and -3 expression and function in osteoclast differentiation using the mouse macrophage cell line RAW264.7 and bone marrow-derived macrophages (BMM). We show that all three SIK are expressed in fully differentiated osteoclasts and that in BMM-derived osteoclasts there is an increased expression of SIK1 and SIK3 proteins. Interestingly, the pan-SIK inhibitor HG-9-91-01 significantly inhibited osteoclastogenesis by dose dependently reducing osteoclast differentiation markers (i.e. CathepsinK, MMP-9 and TRAP) and bone resorbing activity. Analysis of the signaling pathways activated by RANKL in RAW cells showed that SIK inhibitors did not affect RANKL-induced ERK1/2, JNK, p38 or NF-κB activation, but induced a significant downregulation in c-Fos and NFATc1 protein levels, the two main transcription factors involved in the regulation of osteoclast-specific genes. Moreover, SIK inhibition partially increased the proteasome-mediated degradation of c-Fos. SIK2 and SIK3 knockout RAW cells were generated by the CRISPR/Cas9 approach. SIK2 KO and, to a lesser extent, SIK3 KO recapitulated the effect of SIK small molecule inhibitor, thus confirming the specificity of the effect of SIK inhibition on the reduction of osteoclastogenesis. Overall, our results support the notion that the SIK signaling pathway plays a significant role among the check-points controlling osteoclastogenesis. SIK kinase inhibitors could thus represent a potential novel therapy to prevent bone erosions.

Dataset Information

The Triad Na⁺ Activated Na⁺ Channel (Nax)-Salt Inducible KINASE (SIK) and (Na⁺ + K⁺)-ATPase: Targeting the Villains to Treat Salt Resistant and Sensitive Hypertension.

Publications

The Triad Na<sup>+</sup> Activated Na<sup>+</sup> Channel (Nax)-Salt Inducible KINASE (SIK) and (Na<sup>+</sup> + K<sup>+</sup>)-ATPase: Targeting the Villains to Treat Salt Resistant and Sensitive Hypertension.

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