Hypertension is one of the major predisposing factors for neurodegenerative disease characterized with activated renin-angiotensin system (RAS) in both periphery and brain. Vitamin D (VitD) is recently recognized as a pleiotropic hormone with strong neuroprotective properties. While multiple lines of evidence suggest that VitD can act on RAS, the evidence concerning the crosstalk between VitD and RAS in the brain is limited. Therefore, this study aims to evaluate whether VitD can modulate brain RAS to trigger neuroprotective actions in the brain of spontaneously hypertensive rats (SHR). Our data showed that calcitriol treatment induced VDR expression and inhibited neural death in the prefrontal cortex of SHR. Sustained calcitriol administration also inhibited microglia M1 polarization, but enhanced M2 polarization, accompanied with decreased expression of proinflammatory cytokines. We then further explored the potential mechanisms and showed that SHR exhibited overactivated classical RAS with increased expression of angiotensin II (Ang II) receptor type 1 (AT1), angiotensin converting enzyme (ACE) and Ang II production, whereas the counteracting arm of traditional RAS, ACE2/Ang(1-7)/MasR, was impaired in the SHR brain. Calcitriol nonsignificantly suppressed AT1 and ACE but markedly reduced Ang II formation. Intriguingly, calcitriol exerted pronouncedly impact on ACE2/Ang(1-7)/MasR axis with enhanced expression of ACE2, MasR and Ang(1-7) generation. Meanwhile, calcitriol ameliorated the overactivation of NADPH-oxidase (Nox), the downstream of RAS, in SHR, and also mitigated oxidative stress. In microglial (BV2) cells, we further found that calcitriol induced ACE2 and MasR with no significant impact on ACE and AT1. In accordance, calcitriol also attenuated Ang II-induced Nox activation and ROS production, and shifted the microglia polarization from M1 to M2 phenotype. However, co-treatment with A779, a specific MasR antagonist, abrogated the antioxidant and neuroimmune modulating actions of VitD. These findings strongly indicate the involvement of ACE2/Ang(1-7)/MasR pathway in the neuroprotective mechanisms of VitD in the hypertensive brain.

Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: Role of renin-angiotensin system.

Myocardial fibrosis is characterized by excessive deposition of myocardial interstitial collagen, abnormal distribution, and excessive proliferation of fibroblasts. According to the researches in recent years, myocardial fibrosis, as the pathological basis of various cardiovascular diseases, has been proven to be a core determinant in ventricular remodeling. Pressure load is one of the causes of myocardial fibrosis. In experimental models of pressure-overload-induced myocardial fibrosis, significant increase in left ventricular parameters such as interventricular septal thickness and left ventricular posterior wall thickness and the decrease of ejection fraction are some of the manifestations of cardiac damage. These morphological and functional changes have a serious impact on the maintenance of physiological functions. Therefore, establishing a suitable myocardial fibrosis model is the basis of its pathogenesis research. This paper will discuss the methods of establishing myocardial fibrosis model and compare the advantages and disadvantages of the models in order to provide a strong basis for establishing a myocardial fibrosis model.

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Morphological and Functional Characteristics of Animal Models of Myocardial Fibrosis Induced by Pressure Overload.

Central nervous system, peripheral and hemodynamic effects of nanoformulated anandamide in hypertension.

Chronic kidney diseases (CKDs) lead to end-stage renal diseases (ESRD) which are characterized by glomerulosclerosis, tubular injury, anemia, inflammation, and interstitial fibrosis. Vitamin D is known to have renal protective effects. However, its effects relate to low and high doses of Vitamin D in CKD model is still unknown. CKD was performed using 5/6 subtotal nephrectomy procedure in male Sprague Dawley rats (3 months old, 200-300 grams, SN group; n=6), then rats were sacrificed on day 14 after operation. Sham operation was used for control (SO group; n=6). Calcitriol was administered in two doses : 0.01 µg/mL/100 gramsBW/day (SND1 group; n=6) and 0.05 µg/mL/100 gramsBW/day (SND2 group; n=6) intraperitoneally for 14 days. Glomerulosclerosis and tubular injury score were examined using PAS staining, meanwhile, interstitial fibrosis area fraction was assessed with Sirius Red staining. RT-PCR was performed for assessing nephrin, podocin, IL-6, CD68, Collagen-1, and TGF-β1 mRNA expressions. Immunostaining (IHC) was carried out to observe macrophage (CD68) and myofibroblast (α-SMA). SN demonstrated CKD condition with higher tubular injury, glomerulosclerosis, interstitial fibrosis, and inflammation compared to SO. Calcitriol-treated group (especially SND2) demonstrated significant lower tubular injury, glomerulosclerosis, and interstitial fibrosis compared to SN. SND2 group showed not only significantly lower CD68, IL-6, Collagen-1, and TGF-β1 mRNA expressions, but also higher mRNA expressions of nephrin and podocin. SND2 group also demonstrated reduction of macrophages infiltration and myofibroblasts expansion based on its histopathological appearance. Vitamin D may have a renoprotective effect on 5/6 subtotal nephrectomy model by attenuating podocytopathy, tubular injury, inflammation and interstitial fibrosis.

Calcitriol Ameliorates Kidney Injury Through Reducing Podocytopathy, Tubular Injury, Inflammation and Fibrosis in 5/6 Subtotal Nephrectomy Model in Rats.

New advances in the treatment of acute myocardial infarction involve novel signaling pathways and cellular progeny. In this sense, regeneration is a novel tool that would contribute to post-infarction physiological ventricular remodeling. More specifically, re-expression of the WT1 transcription factor in the myocardial wall by ischemia and infarction would be related to the invasion of cells with the capacity for regeneration. This mechanism seems not to be sufficient to restore muscle cells and lost vessels entirely. Of particular interest, the presence of the heat-shock response protein 70 (Hsp70) and its interaction with the vitamin D receptor would modulate the expression of WT1 positively. In this context, it is proposed that the activation of vitamin D receptors associated with Hsp70 could favor physiological cardiac remodeling and reduce the progression to heart failure.

Implications of the transcription factor WT1 linked to the pathologic cardiac remodeling post-myocardial infarction.

Background Hypertension is a major global public health issue. Uncontrolled hypertension leads to organ damage, especially renal damage. Calcitriol is used to treat osteoporosis, promote bone formation, and increase bone mass. Previous studies have demonstrated that 1,25(OH)2D3, in addition to its classic role, also has multiple immune regulation and renoprotective functions and inhibits the activity of the renin-angiotensin-aldosterone system (RASS). The aim of the current study was to investigate the renoprotective effects of calcitriol in a spontaneously hypertensive rat (SHR) model. Methods A total of 18 SHRs and 8 age-matched normal Wistar rats were enrolled. SHRs were randomly divided into a hypertensive nephropathy group (H), a hypertensive nephropathy treated with calcitriol group (D) and a control group (NS). The rats were sacrificed after 16 weeks of treatment. The blood pressure (BP) of rats were measured one time every 4 weeks. The levels of serum albumin, serum creatinine, blood calcium, serum Vitamin D and 24-h urinary protein were measured after 16 weeks treatment. The protein level of WT1, nephrin and vitamin D receptor (VDR) was examined by Western blotting and immunohistochemical staining. Results There were no notable changes in blood pressure or serum creatinine in group H and D compared with group NS. The albumin, calcium and vitamin D serum levels in group H were significantly decreased compared with group NS and significantly increased in group D compared with group H. The level of 24-h urine protein significantly increased in group H compared with group NS and significantly decreased in group D compared with group H. The expression of VDR, WT1 and nephrin in the kidney were all significantly decreased in group H compared with group NS and significantly increased in group D compared with group H. Conclusion The present results indicated that there was injury of podocytes in hypertensive nephropathy, which can be ameliorated by calcitriol in SHR, but there was no significant anti-hypertensive effect. Vitamin D/VDR decreased proteinuria perhaps by increasing expression of nephrin and WT1 protein in podocyte of SHRs.

Protective effect of calcitriol on podocytes in spontaneously hypertensive rat

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Protective effect of calcitriol on podocytes in spontaneously hypertensive rat