apelin-13-peptide and Fibrosis

The pathophysiology of acute respiratory distress syndrome (ARDS) involves cytokine storms, alveolar-capillary barrier destruction, and fibrotic progression. Pulmonary interstitial fibrosis is an important factor affecting the prognosis of ARDS patients. Endothelial-to-mesenchymal transition (EndMT) plays an important role in the development of fibrotic diseases, and the occurrence of EndMT has been observed in experimental models of LPS-induced acute lung injury (ALI). Apelin is an endogenous active polypeptide that plays an important role in maintaining endothelial cell homeostasis and inhibiting fibrotic progression in various diseases. However, whether apelin attenuates EndMT in ALI and post-ALI pulmonary fibrosis remains unclear. We analyzed the serum levels of apelin-13 in patients with sepsis-associated ARDS to examine its possible clinical value. A murine model of LPS-induced pulmonary fibrosis and an LPS-challenged endothelial cell injury model were used to analyze the protective effect and underlying mechanism of apelin-13. Mice were treated with apelin-13 by i.p. injection, and human pulmonary microvascular endothelial cells were incubated with apelin-13 in vitro . We found that the circulating apelin-13 levels were significantly elevated in sepsis-associated ARDS patients compared with healthy controls. Our study also confirmed that LPS induced EndMT progression and pulmonary fibrosis, which were characterized by decreased CD31 expression and increased α-smooth muscle actin expression and collagen deposition. LPS also stimulated the production of transforming growth factor β1 and activated the Smad signaling pathway. However, apelin-13 treatment significantly attenuated these changes. Our findings suggest that apelin-13 may be a novel biomarker in patients with sepsis-associated ARDS. These results demonstrate that apelin-13 ameliorates LPS-induced EndMT and post-ALI pulmonary fibrosis by suppressing transforming growth factor β1 signaling.

Topics: Acute Lung Injury; Animals; Apelin; Endothelial Cells; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Lipopolysaccharides; Mice; Pulmonary Fibrosis; Respiratory Distress Syndrome; Signal Transduction; Transforming Growth Factor beta1

Apelin and its receptor angiotensin receptor - like 1 (APJ) are closely related to renal fibrosis, but their specific roles in renal fibrosis are still controversial. In this article, we discussed the role of Apelin/APJ system in renal fibrosis and its mechanism.. Chronic intermittent hypoxia (CIH) rat model was established to induce the environment of renal fibrosis and a competitive antagonist of the APJ receptor ML221 was administered to CIH rats. The rats were divided into Control, CIH and ML221 groups. HE staining was used to detect the inflammatory injury and fibrosis of renal tissue. The expressions of renal fibrosis-related indicators transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA) and Human type I collagen (Col-Ⅰ) were detected by immunohistochemistry. The levels of oxidative stress indexes reactive oxygen species (ROS), Malondialdehyde (MDA), Superoxide Dismutase (SOD) and inflammation-related indexes Interleukin (IL) -6, tumor necrosis factor-α (TNF-α) and IL-1β were detected by ELISA. At the same time, the levels of Apelin-13 and AngiotensinII (AngⅡ) were also measured by ELISA. Finally, western blot was used to detect the expression of Apelin pathway and renal fibrosis-related proteins. In addition, at the cellular level, we divided the cells into Control, CIH, Apelin-13 and Apelin-13+ML-221 groups to further verify the specific mechanisms at the cellular level.. The expression of Apeline-13 and its related pathways was significantly increased after the induction of CIH in rats. However, the degree of renal fibrosis in ML221 group was further significantly increased after inhibiting the expression of Apelin. At the cellular level, CIH model cells treated with Apelin-13 significantly reduced cell proliferation, oxidative stress and inflammatory response, and decreased the expression of fibrosis-related proteins, which can be reversed by ML221 administration.. The increased reactivity of Apelin may be one of the protective mechanisms against renal fibrosis induced by CIH.

Topics: Angiotensin II; Animals; Apelin; Apelin Receptors; Cell Line; Fibrosis; Humans; Hypoxia; Inflammation; Intercellular Signaling Peptides and Proteins; Kidney; Kidney Diseases; Male; Nitrobenzoates; Oxidative Stress; Pyrans; Rats, Wistar

An increased fibrosis of the corpora cavernosa is a prevalent process that underlies most cases of erectile dysfunction. Apelin, an endogenous circulating peptide, has been documented as an important effector on cardiovascular homeostasis, controlling vascular function and reducing fibrosis in multiple pathological conditions. Recently, initial studies have shown that Apelin, acting through the APJ receptor, also modulates penile erection, however, the role of this system on penile structure and intracorporal collagen remodeling has not been investigated yet.. Here we sought to investigate the effect of chronic Apelin treatment on the corpus cavernosum structure of hyperchOlesterolemic mice.. Local expression of Apelin-13 in mouse corpus cavernosum and its protective effect against fibrosis.. These results point out Apelin/APJ system as a potential target to treat intracavernosal fibrosis-related disorders.. These results provide the first evidence of the Apelin system's positive role on erectile tissue structure/remodeling. Nevertheless, additional functional study addressing erectile response would bring extended validation regarding the relevance of such effect.. These results suggest a local modulation of the Apelin system within the corpus cavernosum. Remarkably, Apelin-13 reduced intracavernosal fibrosis in hypercholesterolemic mice by: (i) enhancing MMPs expression and activity; and (ii) inhibiting fibroblast differentiation into myofibroblast. Altogether, these results suggest an essential protective role of Apelin, indicating Apelin/APJ system as a promising candidate for the development of fibrosis-associated erectile dysfunction treatments. Sturny M, Anguenot L Costa-Fraga FP, et al. Apelin-13 Protects Corpus Cavernosum Against Fibrosis Induced by High-Fat Diet in an MMP-Dependent Mechanism. J Sex Med 2021;18:875-888.

Topics: Animals; Apelin; Diet, High-Fat; Erectile Dysfunction; Fibrosis; Humans; Intercellular Signaling Peptides and Proteins; Male; Matrix Metalloproteinases; Mice; NIH 3T3 Cells; Penile Erection; Penis

Diabetes is a serious metabolic disease, and the kidney damage induced by diabetes also seriously affects the survival of patients. Apelin is a molecule that plays a crucial role in lipid metabolism, and recent studies have revealed that apelin‑13, a subtype of apelin, plays an important role in regulating blood glucose levels. However, the role of apelin‑13 in diabetic nephropathy remains unclear. In the present study, a rat model of diabetic nephropathy was constructed by the injection of streptozocin (STZ). During this process, these rats were injected with apelin‑13. The blood glucose, urine protein and insulin levels were determined weekly. Next, the expression of angiotensin domain type 1 receptor‑associated protein (APJ), endothelial nitric oxide synthase (eNOS), E‑cadherin and α‑smooth muscle actin (α‑SMA) in the kidney tissues was determined with western blotting. Then, the endothelial cells of glomerular vessels were cultured with high glucose medium. These cells were treated with apelin‑13 for 24 h. Finally, cell viability of these cells and the expression of APJ, eNOS, E‑cadherin and α‑SMA in these cells were determined with western blotting. As a result, treatment of apelin‑13 induced the lower levels of blood glucose and urine protein. In addition, application of apelin‑13 promoted the production of insulin and alleviated the insulin resistance. Treatment with apelin‑13 promoted the expression of APJ, eNOS and E‑cadherin while it suppressed the expression of α‑SMA in kidney tissues of rats and endothelial cells of glomerular vessels. Furthermore, application of apelin‑13 also promoted the cell viability of these cells. In conclusion, apelin‑13 relieved diabetic nephropathy by promoting the production of nitric oxide (NO) and alleviating the fibrosis of kidney tissues.

Topics: Animals; Antifibrotic Agents; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fibrosis; Intercellular Signaling Peptides and Proteins; Kidney; Male; Nitric Oxide; Rats; Rats, Sprague-Dawley

The present study aimed to determine whether apelin-13 could attenuate cardiac fibrosis via inhibiting the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway to inhibit reactive oxygen species in heart failure (HF) rats. HF models were established by inducing ischemia myocardial infarction (MI) through ligation of the left anterior descending artery in Sprague-Dawley (SD) rats. MI-induced changes in hemodynamics and cardiac function were reversed by apelin-13 administration. The increases in the levels of collagen I, collagen III, α-smooth muscle actin (SMA), and transforming growth factor-β (TGF-β) in the heart of MI rats and cardiac fibroblasts (CFs) treated with angiotensin (Ang) II were inhibited by apelin-13. The levels of PI3K and p-Akt increased in Ang II-treated CFs, and these increases were blocked by apelin-13. The PI3K overexpression reversed the effects of apelin-13 on Ang II-induced increases in collagen I, collagen III, α-SMA, and TGF-β, NADPH oxidase activity and superoxide anions in CFs. Apelin-13 reduced the increases in the levels of NADPH oxidase activity and superoxide anions in the heart of MI rats and CFs with Ang II treatment. The results demonstrated that apelin-13 improved cardiac dysfunction, impaired cardiac hemodynamics, and attenuated fibrosis of CFs induced by Ang II via inhibiting the PI3K/Akt signaling pathway to inhibit oxidative stress.

Topics: Angiotensin II; Animals; Disease Models, Animal; Echocardiography; Fibroblasts; Fibrosis; Heart; Heart Failure; Humans; Injections, Intraperitoneal; Intercellular Signaling Peptides and Proteins; Male; Myocardial Infarction; Myocardium; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction

Apelin has been proved to be a critical mediator of vascular function and homeostasis. Here, we investigated roles of Apelin in aortic remodeling and fibrosis in rats with transverse aortic constriction (TAC). Male Sprague-Dawley rats were subjected to TAC and then randomized to daily deliver Apelin-13 (50μg/kg) or angiotensin type 1 receptor (AT1) blocker Irbesartan (50mg/kg) for 4 weeks. Pressure overload resulted in myocardial hypertrophy, systolic dysfunction, aortic remodeling and adventitial fibrosis with reduced levels of Apelin in ascending aortas of rat after TAC compared with sham-operated group. These changes were associated with marked increases in levels of miRNA-122, TGFβ1, CTGF, NFAT5, LGR4, and β-catenin. More importantly, Apelin and Irbesartan treatment strikingly prevented TAC-mediated aortic remodeling and adventitial fibrosis in pressure overloaded rats by blocking AT1 receptor and miRNA-122 levels and repressing activation of the CTGF-NFAT5 and LGR4-β-catenin signaling. In cultured primary rat adventitial fibroblasts, exposure to angiotensin II (100nmolL

Topics: Adventitia; Animals; Aorta; Aortic Aneurysm, Thoracic; beta Catenin; Cardiomegaly; Cells, Cultured; Fibrosis; Intercellular Signaling Peptides and Proteins; Male; MicroRNAs; Myocardium; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Transcription Factors; Vascular Remodeling; Ventricular Remodeling; Wnt Signaling Pathway

It is known that apelin has definite protective effects on various cardiovascular diseases; however, the mechanism through which hypertension with heart failure (H-HF) is affected by pyroglutamylated apelin-13 (Pyr-AP13) remain unclear. Thus, in the present study, we investigated the effects of apelin on the cardiac hemodynamics in rats with hypertension and heart failure. In our study, cardiac function, dimensions and histological determination of the fibrosis of rats with two-kidney, one-clip induced hypertension and sham-operated rats were assessed using an echocardiography system and Masson's trichrome. The infusion of either 5% glucose injection (GS) alone or 5% GS containing Pyr-AP13 as a dose, time-matched design on the cardiac hemodynamics in H-HF rats and sham-operated rats was recorded. For the determination of the effects of potential related proteins on cardiac hemodynamics in the H-HF rats, the animals were divided into 5 groups: i) the sham-operated group (n=8); ii) H-HF (n=8); iii) H-HF with infusion of 0.1 µg dose of Pyr-AP13 (n=8) or 5% glucose (GS) (n=8); iv) H-HF with infusion of 1 µg dose of Pyr-AP13 (n=8) or 5% GS (n=8); and v) H-HF with infusion of 10 µg dose of Pyr-AP13 (n=8) or 5% GS (n=8). The concentration of cyclic adenosine 3',5'-monophosphate (cAMP) was determined by ELISA. The expression of membrane and cytosolic proteins was evaluated by western blot analysis. Significant cardiac and perivascular fibrosis was observed in the H-HF rats. Following the infusion of Pyr-AP13, the systolic and diastolic function was significantly improved in the cardiac hemodynamic parameters in the H-HF rats treated with Pyr-AP13. The apelin receptor (APJ), which was activated by the exogenous infusion of Pyr-AP13, was partially recycled from the cytoplasm back to the plasma membrane; however, membrane APJ was eventually downregulated in the H-HF rats treated with Pyr-AP13 compared with the sham-operated group rats. Our findings suggested that a complex was formed after Pyr-AP13 combined with cellular membrane APJ receptor. However, the endogenous downregulation of the APJ receptor results in benefits from the exogenous administration of apelin.

Topics: Animals; Apelin Receptors; Cardiotonic Agents; Cell Separation; Cyclic AMP; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Heart; Heart Failure; Hemodynamics; Hypertension; Intercellular Signaling Peptides and Proteins; Male; Myocytes, Cardiac; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Time Factors; Ultrasonography; Ventricular Function, Left

Epithelial-mesenchymal transition (EMT) of tubular epithelial cells is a key event in renal interstitial fibrosis and the progression of chronic kidney disease (CKD). Apelin is a regulatory peptide involved in the regulation of normal renal hemodynamics and tubular functions, but its role in renal fibrosis remains unknown. In this study, we examined the inhibitory effects of apelin on transforming growth factor-β1 (TGF-β1)-induced EMT in HK-2 cells, and evaluated its therapeutic efficacy in mice with complete unilateral ureteral obstruction (UUO). In vitro, apelin inhibited TGF-β1-mediated upregulation of α-smooth muscle actin (α-SMA) and downregulation of E-cadherin. Increased levels of phosphorylated Smad-2/3 and decreased levels of Smad7 in TGF-β1-stimulated cells were reversed by apelin co-treatment. In the UUO model, administration of apelin significantly attenuated renal interstitial fibrosis, as evidenced by the maintenance of E-cadherin and laminin expression, and markedly suppressed expression of α-SMA, TGF-β1 and its type I receptor, as well as interstitial matrix components. Interestingly, in UUO mice, there was a reduction in the plasma level of apelin, which was compensated by upregulation of APJ expression in the injured kidney. Exogenous supplementation of apelin normalized the level of plasmatic apelin and renal APJ. In conclusion, our study provides the first evidence that apelin is able to ameliorate renal interstitial fibrosis by suppression of tubular EMT through a Smad-dependent mechanism. The apelinergic system itself may promote some compensatory response in the renal fibrotic process. These results suggest that apelin has potential renoprotective effects and may be an effective agent for retarding CKD progression.

Topics: Animals; Cadherins; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Intercellular Signaling Peptides and Proteins; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Smad Proteins; Transforming Growth Factor beta1

Apelin is an endogenous ligand for the angiotensin-like 1 receptor (APJ) and has beneficial effects against myocardial ischemia-reperfusion injury. Little is known about the role of apelin in the homing of vascular progenitor cells (PCs) and cardiac functional recovery postmyocardial infarction (post-MI). The present study investigated whether apelin affects PC homing to the infarcted myocardium, thereby mediating repair and functional recovery post-MI. Mice were infarcted by coronary artery ligation, and apelin-13 (1 mg·kg(-1)·day(-1)) was injected for 3 days before MI and for 14 days post-MI. Homing of vascular PCs [CD133(+)/c-Kit(+)/Sca1(+), CD133(+)/stromal cell-derived factor (SDF)-1α(+), and CD133(+)/CXC chemokine receptor (CXCR)-4(+)] into the ischemic area was examined. Myocardial Akt, endothelial nitric oxide synthase (eNOS), VEGF, jagged1, notch3, SDF-1α, and CXCR-4 expression were assessed at 24 h and 14 days post-MI. Functional analyses were performed on day 14 post-MI. Mice that received apelin-13 treatment demonstrated upregulation of SDF-1α/CXCR-4 expression and dramatically increased the number of CD133(+)/c-Kit(+)/Sca1(+), CD133(+)/SDF-1α(+), and c-Kit(+)/CXCR-4(+) cells in infarcted hearts. Apelin-13 also significantly increased Akt and eNOS phosphorylation and upregulated VEGF, jagged1, and notch3 expression in ischemic hearts. This was accompanied by a significant reduction of myocardial apoptosis. Furthermore, treatment with apelin-13 promoted myocardial angiogenesis and attenuated cardiac fibrosis and hypertrophy together with a significant improvement of cardiac function at 14 days post-MI. Apelin-13 increases angiogenesis and improves cardiac repair post-MI by a mechanism involving the upregulation of SDF-1α/CXCR-4 and homing of vascular PCs.

Topics: AC133 Antigen; Adipokines; Animals; Antigens, CD; Antigens, Ly; Apelin; Apoptosis; Biomarkers; Calcium-Binding Proteins; Cardiomegaly; Cardiotonic Agents; Cell Movement; Cells, Cultured; Chemokine CXCL12; Disease Models, Animal; Fibrosis; Glycoproteins; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Membrane Proteins; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocytes, Cardiac; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Peptides; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-kit; Receptor, Notch3; Receptors, CXCR4; Receptors, Notch; Recovery of Function; Regeneration; Serrate-Jagged Proteins; Stem Cells; Time Factors; Vascular Endothelial Growth Factor A; Ventricular Function, Left