Bradykinin, as a Reprogramming Factor, Induces Transdifferentiation of Brain Astrocytes into Neuron-Like Cells

Kinins are endogenous, biologically active peptides released into the plasma and tissues via the kallikrein-kinin system in several pathophysiological events. Among kinins, bradykinin (BK) is widely distributed in the periphery and brain. Several studies on the neuro-modulatory actions of BK by the B2BK receptor (B2BKR) indicate that this neuropeptide also functions during neural fate determination. Previously, BK has been shown to induce differentiation of nerve-related stem cells into neuron cells, but the response in mature brain astrocytes is unknown. Herein, we used rat brain astrocyte (RBA) to investigate the effect of BK on cell transdifferentiation into a neuron-like cell morphology. Moreover, the signaling mechanisms were explored by zymographic, RT-PCR, Western blot, and immunofluorescence staining analyses. We first observed that BK induced RBA transdifferentiation into neuron-like cells. Subsequently, we demonstrated that BK-induced RBA transdifferentiation is mediated through B2BKR, PKC-δ, ERK1/2, and MMP-9. Finally, we found that BK downregulated the astrocytic marker glial fibrillary acidic protein (GFAP) and upregulated the neuronal marker neuron-specific enolase (NSE) via the B2BKR/PKC-δ/ERK pathway in the event. Therefore, BK may be a reprogramming factor promoting brain astrocytic transdifferentiation into a neuron-like cell, including downregulation of GFAP and upregulation of NSE and MMP-9 via the B2BKR/PKC-δ/ERK cascade. Here, we also confirmed the transdifferentiative event by observing the upregulated neuronal nuclear protein (NeuN). However, the electrophysiological properties of the cells after BK treatment should be investigated in the future to confirm their phenotype.

Download Full-text

PERTURBATION OF THE KALLIKREIN-KININ SYSTEM IN ADULT RESPIRATORY DISTRESS SYNDROME (ARDS)

10.1055/s-0038-1644336 ◽

1987 ◽

Author(s):

K Walshe ◽

I Mackie ◽

M Gallimore ◽

S J Machin

Keyword(s):

Transplant Rejection ◽

Prognostic Significance ◽

Biologically Active ◽

Smoke Inhalation ◽

Kinin System ◽

Active Peptides ◽

Large Numbers ◽

Biologically Active Peptides ◽

Kallikrein Kinin System ◽

Renal Transplant Rejection

Platelet and fibrin deposition in the small blood vessels of the lung as well as activation of the contact system with consequent kinin generation have been described in ARDS. It is thought that these haemostatic changes may play a role in the pathogenesis of the disease which include dyspnoea, hypoxaemia, pulmonary oedema, and pulmonary hypertension. We have studied a complete battery of tests for the proteases and inhibitors of the kallikrein-kinin system in an ongoing study of ARDS and haemostasis. 12 patients have so far been studied, with the following factors complicating ARDS: 5 had sepsis, 3 post surgical, 1 head injury, chronic renal and airways disease, renal transplant rejection, or after smoke inhalation during a fire. Assays for: FXI, FXII, prekallikrein (PKK), kallikrein inhibitor (KKi), betaFXIIa inhibitor, (BXIIAi), alpha-2-macroglobulin (α-2-M), alpha-l-antitrypsin (α-1-AT), and antithrombin III (ATIII) were performed by microtitre amidolytic assays to allow the economic processing of large numbers of samples. FXII, PKK, ATIII and α-2-M were invariably low, returning towards normal as the patient became clinically well. The PKK level in particular reflected the clinical course of the patient and appeared to have prognostic significance. Surprisingly, the BXIIai and KKi tended to be increased when the FXII and PKK were decreased. FXI and -1-AT levels showed no change. These results suggest that clinical concentrates of haemostatic inhibitors may be of benefit in ARDS, to stop the continuous activation of the kallikrein-kinin system and generation of biologically active peptides.

Download Full-text

The renin-angiotensin system and its blockers

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh1412756i ◽

2014 ◽

Vol 142 (11-12) ◽

pp. 756-763 ◽

Cited By ~ 9

Author(s):

Rajko Igic ◽

Ranko Skrbic

Keyword(s):

Angiotensin Ii ◽

Renin Angiotensin System ◽

Biologically Active ◽

Kinin System ◽

Angiotensin System ◽

Renin Angiotensin ◽

Active Peptides ◽

History Of ◽

Essential Connection ◽

Kallikrein Kinin System

Research on the renin-angiotensin system (RAS) has contributed significantly to advances in understanding cardiovascular and renal homeostasis and to the treatment of cardiovascular diseases. This review offers a brief history of the RAS with an overview of its major components and their functions, as well as blockers of the RAS, their clinical usage and current research that targets various components of the RAS. Because angiotensin-converting enzyme (ACE) metabolizes two biologically active peptides, one in the kallikrein-kinin system (KKS) and one in the RAS, it is the essential connection between the two systems. ACE releases very powerful hypertensive agent, angiotensin II and also inactivates strong hypotensive peptide, bradykinin. Inhibition of ACE thus has a dual effect, resulting in decreased angiotensin II and increased bradykinin. We described the KKS as well.

Download Full-text