Salt-inducible kinases: new players in pulmonary arterial hypertension?

Salt-inducible kinases (SIKs) are serine/threonine kinases belonging to the AMP-activated protein kinase (AMPK) family. Accumulating evidence indicates that SIKs phosphorylate multiple targets, including histone deacetylases (HDACs) and cAMP response element-binding protein (CREB)-regulated transcriptional coactivators (CRTCs), to coordinate signaling pathways implicated in metabolism, cell growth, proliferation, apoptosis, and inflammation. These pathways downstream of SIKs are altered not only in pathologies like cancer, systemic hypertension, and inflammatory diseases, but also in pulmonary arterial hypertension (PAH), a multifactorial disease characterized by pulmonary vasoconstriction, inflammation and remodeling of pulmonary arteries owing to endothelial dysfunction and aberrant proliferation of smooth muscle cells (SMCs). In this opinion article, we present evidence of SIKs as modulators of key signaling pathways involved in PAH pathophysiology and discuss the potential of SIKs as therapeutic targets for PAH, emphasizing the need for deeper molecular insights on PAH.

The role of salt-inducible kinases on the modulation of renal and intestinal Na+,K+-ATPase activity during short- and long-term high-salt intake.

Type 1 salt-inducible kinases (SIK1) has been shown to act as a mediator during the cellular adaptation to variations in intracellular sodium in a variety of cell types. Type 2 SIK (SIK2) modulates various biological functions and acts as a signal transmitter in various pathways. To evaluate the role of both SIK isoforms in renal and intestinal Na+,K+-ATPase (NKA) activity, we made use of constitutive sik1-/- (SIK1-KO), sik2-/- (SIK2-KO), double sik1-/-sik2-/- (double SIK1*2-KO) knockout and wild-type (WT) mice challenged to a standard (0.3% NaCl) or chronic high-salt (HS, 8% NaCl) diet intake for 48 h or 12 weeks. Long-term HS intake in WT was accompanied by 2-fold increase in jejunal NKA activity and slight (~30% reduction) decreases in NKA in the ileum and cecum; none of these changes was accompanied by changes in the expression of α1-NKA. The ablation of SIK1 and SIK2 prevented the marked increase in jejunal NKA activity following the long-term HS intake. The ablation of SIK1 and SIK2 in mice on a long-term HS intake impacted differently in the ileum and cecum. The most interesting finding is that in SIK2-KO mice marked reductions in NKA activity were observed in the ileum and cecum when compared to WT mice, both on normal and long-term HS intake. In summary, SIK1 or SIK2 ablation on chronic high-salt intake is accompanied by modulation of NKA along the intestinal tract, which differ from those after an acute high-salt intake, and this may represent an absorptive compensatory mechanism to keep electrolyte homeostasis.

Acute salt loading induces sympathetic nervous system overdrive in mice lacking salt-inducible kinase 1 (SIK1).

Loss of salt-inducible kinase 1 (SIK1) triggers an increase in blood pressure (BP) upon a chronic high-salt intake in mice. Here, we further addressed the possible early mechanisms that may relate to the observed rise in BP in mice lacking SIK1. SIK1 knockout (sik1-/-) and wild-type (sik1+/+) littermate mice were challenged with either a high-salt (8% NaCl) or control (0.3% NaCl) diet for 7 days. Systolic BP was significantly increased in sik1-/- mice after 7 days of high-salt diet as compared with sik1+/+ mice and to sik1-/- counterparts on a control diet. The renin-angiotensin-aldosterone system and the sympathetic nervous system were assayed to investigate possible causes for the increase in BP in sik1-/- mice fed a 7-day high-salt diet. Although no differences in serum renin and angiotensin II levels were observed, a reduction in aldosterone serum levels was observed in mice fed a high-salt diet. Urinary L-DOPA and noradrenaline levels were significantly increased in sik1-/- mice fed a high-salt diet as compared with sik1-/- mice on a control diet. Similarly, the activity of dopamine ß-hydroxylase (DßH), the enzyme that converts dopamine to noradrenaline, was significantly increased in the adrenal glands of sik1-/- mice on a high-salt intake compared with sik1+/+ and sik1-/- mice on a control diet. Treatment with etamicastat (50 mg/kg/day), a peripheral reversible DßH inhibitor, administered prior to high-salt diet, completely prevented the systolic BP increase in sik1-/- mice. In conclusion, SIK1 activity is necessary to prevent the development of salt-induced high blood pressure and associated SNS overactivity.

Evaluation of different media for the production of cephalosporins by Streptomyces clavuligerus ATCC 27064

The aim of this work was to compare the composition of a complex and soluble culture medium to eight other media described in the literature through the batch cultivation in a conventional bench-scale bioreactor for the production of cephamycin C by a wild strain of Streptomyces clavuligerus. The proposed medium resulted in an antibiotic production 1.5 to 7.5 times higher than the other culture media.