Mechanism Actions of Coniferyl Alcohol in Improving Cardiac Dysfunction in Renovascular Hypertension Studied by Experimental Verification and Network Pharmacology.

Renovascular hypertension (RH), a secondary hypertension, can significantly impact heart health, resulting in heart damage and dysfunction, thereby elevating the risk of cardiovascular diseases. Coniferol (CA), which has vascular relaxation properties, is expected to be able to treat hypertension-related diseases. However, its potential effects on cardiac function after RH remain unclear. In this study, in combination with network pharmacology, the antihypertensive and cardioprotective effects of CA in a two-kidney, one-clip (2K1C) mice model and its ability to mitigate angiotensin II (Ang II)-induced hypertrophy in H9C2 cells were investigated. The findings revealed that CA effectively reduced blood pressure, myocardial tissue damage, and inflammation after RH. The possible targets of CA for RH treatment were screened by network pharmacology. The interleukin-17 (IL-17) and tumor necrosis factor (TNF) signaling pathways were identified using a Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The inflammatory response was identified using a Gene Ontology (GO) enrichment analysis. Western blot analysis confirmed that CA reduced the expression of IL-17, matrix metallopeptidase 9 (MMP9), cyclooxygenase 2 (COX2), and TNF α in heart tissues and the H9C2 cells. In summary, CA inhibited cardiac inflammation and fibrohypertrophy following RH. This effect was closely linked to the expression of MMP9/COX2/TNF α/IL-17. This study sheds light on the therapeutic potential of CA for treating RH-induced myocardial hypertrophy and provides insights into its underlying mechanisms, positioning CA as a promising candidate for future drug development.

Fenofibrate reduces cardiac remodeling by mitochondrial dynamics preservation in a renovascular model of cardiac hypertrophy.

Fenofibrate, a PPAR-α agonist clinically used to lower serum lipid levels, reduces cardiac remodeling and improves cardiac function. However, its mechanism of action is not completely elucidated. In this study we examined the effect of fenofibrate on mitochondria in a rat model of renovascular hypertension, focusing on mediators controlling mitochondrial dynamics and autophagy. Rats with two-kidney one-clip (2K1C) hypertension were treated with fenofibrate 150 mg/kg/day (2K1C-FFB) or vehicle (2K1C-VEH) for 8 weeks. Systolic blood pressure and cardiac functional were in-vivo assessed, while cardiomyocyte size and protein expression of mediators of cardiac hypertrophy and mitochondrial dynamics were ex-vivo examined by histological and Western blot analyses. Fenofibrate treatment counteracted the development of hypertension and the increase of left ventricular mass, relative wall thickness and cross-sectional area of cardiomyocytes. Furthermore, fenofibrate re-balanced the expression Mfn2, Drp1 and Parkin, regulators of fusion, fission, mitophagy respectively. Regarding autophagy, the LC3-II/LC3-I ratio was increased in 2K1C-VEH and 2K1C-FFB, whereas the autophagy was increased only in 2K1C-FFB. In cultured H9C2 cardiomyoblasts, fenofibrate reversed the Ang II-induced mRNA up-regulation of hypertrophy markers Nppa and Myh7, accumulation of reactive oxygen species and depolarization of the mitochondrial membrane exerting protection mediated by up-regulation of the Uncoupling protein 2. Our results indicate that fenofibrate acts directly on cardiomyocytes and counteracts the pressure overload-induced cardiac maladaptive remodeling. This study reveals a so far hidden mechanism involving mitochondrial dynamics in the beneficial effects of fenofibrate, support its repurposing for the treatment of cardiac hypertrophy and provide new potential targets for its pharmacological function.

Comparative assessment of CacyBP/SIP, ß-catenin and cannabinoid receptors in the adrenals of hypertensive rats.

Taking into account homeostatic disorders resulting from arterial hypertension and the key importance of CacyBP/SIP, ß-catenin and endocannabinoids in the functioning of many organs, it was decided to assess the presence and distribution of CacyBP/SIP, ß-catenin, CB1 and CB2 in the adrenal glands of hypertensive rats of various aetiology. The study was conducted on the adrenal glands of rats with spontaneous and renovascular hypertension. The expression of CacyBP/SIP, ß-catenin, CB1 and CB2 was detected by immunohistochemistry and real-time PCR method. The results of the present study revealed both lower gene expression and immunoreactivity of CacyBP/SIP in the adrenal glands of all hypertensive groups compared to the normotensive rats. This study demonstrated a reduction in the immunoreactivity and expression of the ß-catenin, CB1 and CB2 genes in the adrenals of 2K1C rats. While in SHR, the reaction showing ß-catenin and CB1 was very weak or negative, and the expression of CB2 in the adrenal glands of these rats increased. The results of this study show, for the first time, marked differences in the expression of CacyBP/SIP, ß-catenin and CB1 and CB2 cannabinoid receptors in the adrenal glands of rats with primary (SHR) and secondary hypertension (2K1C).

Endovascular interventions in main renal artery pathologies: an overview and update.

Renal arteries are involved in a wide spectrum of pathologies including atherosclerosis, fibromuscular dysplasia, Takayasu arteritis, aneurysms, and aortic type B dissections extending into main renal arteries. They manifest as renovascular hypertension, renal ischemia, and cardiovascular dysfunction. The location of the renal arteries in relation to the abdominal aortic aneurysm is a critical determinant of interventional options and long-term prognosis. This article provides a comprehensive review of the role of interventional radiologists in transcatheter interventions in various pathologies involving the main renal arteries with analysis of epidemiology, pathophysiology, newer interventional techniques, and management options.

Bone marrow-derived mesenchymal stem cells transplantation ameliorates renal injury through anti-fibrotic and anti-inflammatory effects in chronic experimental renovascular disease.

BACKGROUND: Progressive renal fibrosis is an underlying pathological process of chronic kidney disease (CKD) evolution. This study aimed to evaluate the roles of bone-marrow-derived mesenchymal stem cells (MSC) in the remodeling of fibrotic kidney parenchyma in the two kidneys-one clip (2K1C) CKD animal model. METHODS: Wistar rats were allocated into three groups: Sham, 2K1C, and 2K1C þ MSC. MSCs (106) were transplanted into the renal subcapsular region two weeks after clipping the left renal artery. Six weeks after clipping, left kidney samples were analyzed using histological and western blotting techniques. ANOVA tests were performed and differences between groups were considered statistically significant if p < 0.05. RESULTS: Clipped kidneys of 2K1C rats displayed renal fibrosis, with excessive collagen deposition, glomerulosclerosis and renal basement membrane disruption. Clipped kidneys of 2K1C þ MSC rats showed preserved Bowman's capsule and tubular basement membranes, medullary tubules morphological reconstitution and reduced collagen deposits. Expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 were elevated, whereas tissue inhibitor of MMPs (TIMP)-1 and TIMP-2 levels were decreased in clipped kidneys of 2K1C rats. MSCs transplantation restored these expression levels. Moreover, MSCs suppressed macrophages and myofibroblasts accumulation, as well as TNF-a expression in clipped kidneys of 2K1C animals. MSCs transplantation significantly increased IL-10 expression. CONCLUSIONS: Transplanted MSCs orchestrate anti-fibrotic and anti-inflammatory events, which reverse renal fibrosis and promote renal morphological restoration. This study supports the notion that only one MSCs delivery into the renal subcapsular region represents a possible therapeutic strategy against renal fibrosis for CKD treatment.

Radiation-induced kidney toxicity: molecular and cellular pathogenesis.

Radiation nephropathy (RN) is a kidney injury induced by ionizing radiation. In a clinical setting, ionizing radiation is used in radiotherapy (RT). The use and the intensity of radiation therapy is limited by normal-tissue damage including kidney toxicity. Different thresholds for kidney toxicity exist for different entities of RT. Histopathologic features of RN include vascular, glomerular and tubulointerstitial damage. The different molecular and cellular pathomechanisms involved in RN are not fully understood. Ionizing radiation causes double-stranded breaks in the DNA, followed by cell death including apoptosis and necrosis of renal endothelial, tubular and glomerular cells. Especially in the latent phase of RN oxidative stress and inflammation have been proposed as putative pathomechanisms, but so far no clear evidence was found. Cellular senescence, activation of the renin-angiotensin-aldosterone-system and vascular dysfunction might contribute to RN, but only limited data is available. Several signalling pathways have been identified in animal models of RN and different approaches to mitigate RN have been investigated. Drugs that attenuate cell death and inflammation or reduce oxidative stress and renal fibrosis were tested. Renin-angiotensin-aldosterone-system blockade, anti-apoptotic drugs, statins, and antioxidants have been shown to reduce the severity of RN. These results provide a rationale for the development of new strategies to prevent or reduce radiation-induced kidney toxicity.

Different reactive species modulate the hypotensive effect triggered by angiotensins at CVLM of 2K1C hypertensive rats.

Hypertension is associated with increased central activity of the renin-angiotensin system (RAS) and oxidative stress. Here, we evaluated whether reactive species and neurotransmitters could contribute to the hypotensive effect induced by angiotensin (Ang) II and Ang-(1-7) at the caudal ventrolateral medulla (CVLM) in renovascular hypertensive rats (2K1C). Therefore, we investigated the effect of Ang II, Ang-(1-7), and the Ang-(1-7) antagonist A-779 microinjected before and after CVLM microinjection of the nitric oxide (NO)-synthase inhibitor, (L-NAME), vitamin C (Vit C), bicuculline, or kynurenic acid in 2K1C and SHAM rats. Baseline values of the mean arterial pressure (MAP) in 2K1C rats were higher than in SHAM rats. CVLM microinjection of Ang II, Ang-(1-7), l-NAME, or bicuculline induced decreases in the MAP in SHAM and 2K1C rats. In addition, Vit C and A-779 produced decreases in the MAP only in 2K1C rats. Kynurenic acid increased the MAP in both SHAM and 2K1C rats. Only the Ang-(1-7) effect was increased by l-NAME and reduced by bicuculline in SHAM rats. L-NAME also reduced the A-779 effect in 2K1C rats. Only the Ang II effect was abolished by CVLM Vit C and enhanced by CVLM kynurenic acid in SHAM and 2K1C rats. Overall, the superoxide anion and glutamate participated in the hypotensive effect of Ang II, while NO and GABA participated in the hypotensive effect of Ang-(1-7) in CVLM. The higher hypotensive response of A-779 in the CVLM of 2K1C rats suggests that Ang-(1-7) contributes to renovascular hypertension.

Kidney enlargement effect of angioplasty for nonatherosclerotic renovascular disease: reversibility of ischemic kidney.

Renal artery stenosis causes kidney ischemia, reducing the size of the affected kidney, which eventually results in atrophy. Although renal atrophy is considered irreversible, resolution of the ischemia occasionally restores kidney size when the cause is renal artery stenosis. Angioplasty is effective in patients with nonatherosclerotic renovascular diseases (non-ARVDs). Nevertheless, renal enlargement after angioplasty has not been fully examined. We conducted a retrospective study to examine this phenomenon in non-ARVD patients. Ten patients with a <100-mm pole-to-pole length of the poststenotic kidney were treated with angioplasty. Data were collected up to 12 months after angioplasty. The mean age was 28 years; the estimated glomerular filtration rate was 92 ± 7 mL/min/1.73 m2 (mean ± SEM); blood pressure was 150/99 mmHg; 80% were women; and fibromuscular dysplasia was present in 90% of the patients. All patients had hypertension. The lengths of the poststenotic and contralateral kidney before angioplasty were 91 ± 1 and 111 ± 3 mm, respectively. After angioplasty, the length of the poststenotic kidney gradually increased during the 3 months after treatment (+5.4 mm) and that of the contralateral kidney decreased over the same time course (-3.7 mm). Enlargement was also found in the moderate atrophy subgroup (length < 92 mm), and it was greater in the <30 years old group. In a noteworthy case, renal size in the poststenotic kidney recovered from 87 to 102 mm after angioplasty. Our findings demonstrated that reduced renal size can be reversed after optimal angioplasty in non-ARVD patients, especially young patients, suggesting reversibility of the ischemic kidney.

Experimental Renovascular Disease Induces Endothelial Cell Mitochondrial Damage and Impairs Endothelium-Dependent Relaxation of Renal Artery Segments.

BACKGROUND: Mitochondria modulate endothelial cell (EC) function, but may be damaged during renal disease. We hypothesized that the ischemic and metabolic constituents of swine renovascular disease (RVD) induce mitochondrial damage and impair the function of renal artery ECs. METHODS: Pigs were studied after 16 weeks of metabolic syndrome (MetS), renal artery stenosis (RAS), or MetS + RAS, and Lean pigs served as control (n = 6 each). Mitochondrial morphology, homeostasis, and function were measured in isolated primary stenotic-kidney artery ECs. EC functions were assessed in vitro, whereas vasoreactivity of renal artery segments was characterized in organ baths. RESULTS: Lean + RAS and MetS + RAS ECs showed increased mitochondrial area and decreased matrix density. Mitochondrial biogenesis was impaired in MetS and MetS + RAS compared with their respective controls. Mitochondrial membrane potential similarly decreased in MetS, Lean + RAS, and MetS + RAS groups, whereas production of reactive oxygen species increased in MetS vs. Lean, but further increased in both RAS groups. EC tube formation was impaired in MetS, RAS, and MetS + RAS vs. Lean, but EC proliferation and endothelial-dependent relaxation of renal artery segments were blunted in MetS vs. Lean, but further attenuated in Lean + RAS and MetS + RAS. CONCLUSIONS: MetS and RAS damage mitochondria in pig renal artery ECs, which may impair EC function. Coexisting MetS and RAS did not aggravate EC mitochondrial damage in the short time of our in vivo studies, suggesting that mitochondrial injury is associated with impaired renal artery EC function.

Aliskiren improves renal morphophysiology and inflammation in Wistar rats with 2K1C renovascular hypertension.

Hypertension is characterized by persistent elevated blood pressure levels, one of the leading causes of death in the world. Renovascular hypertension represents the most common cause of secondary hypertension, and its progress is associated with overactivation of the renin angiotensin aldosterone system (RAAS), causing systemic and local changes. Aliskiren is a renin-inhibiting drug that optimizes RAAS suppression. In this sense, the objective of the present study was to analyze the morphophysiology of the left kidney in Wistar rats with renovascular hypertension after treatment with Aliskiren. Parameters such as systolic blood pressure, urinary creatinine and protein excretion, renal cortex structure and ultrastructure, fibrosis and tissue inflammation were analyzed. Our results showed that the hypertensive animals treated with Aliskiren presented a reestablishment of blood pressure, expression of renin, and renal function, as well as a remodeling of morphological alterations through the reduction of fibrosis. The treatment regulated the laminin expression and decreased pro-inflammatory cytokines, restoring the integrity of the glomerular filtration barrier. Therefore, our findings suggest that Aliskiren has a renoprotective effect acting on the improvement of the morphology, physiology and pathology of the renal cortex of animals with renovascular hypertension.