Apelin/APJ system: A novel potential therapy target for kidney disease

3.1 Apelin/APJ system attenuates renal fibrosis

Renal fibrosis is a major hallmark in the occurrence and progression of CKD (Mack & Yanagita, 2015; Roberts, Cowan, Alexander, Robson, & Dwyer, 2014). Extracellular matrix (ECM) protein is a typical marker of renal fibrosis, which increased the degree of renal damage in the glomerular and renal interstitial abnormalities (Sun, Qu, Caruana, & Li, 2016). The endless healing process causes renal fibrosis when the normal wound healing response fails. Studies indicate that the level of apelin is elevated when mice are subject to UUO surgery and then treat with subsequent losartan treatment. Furthermore, losartan alleviates UUO-induced renal fibrosis via the apelin/APJ/Akt/eNOS pathway (Huang, Chen, Lu, & Li, 2016a). And apelin/APJ system can activate the endothelial nitric oxide synthase (eNOS) pathway (Ashley, Chun, & Quertermous, 2006; Huang et al., 2016a). Apelin/APJ system, interacting with losartan exerts a synergistic effect in attenuating renal fibrosis (Nishida et al., 2012). In vitro, apelin inhibits epithelial–mesenchymal transition (EMT) induced by the TGF-β (transforming growth factor-β) in HK-2 cells. In the UUO model, apelin significantly reduces the expression of TGF-β1 and its receptor, as well as interstitial matrix components. Apelin also ameliorates renal interstitial fibrosis by suppressing tubular EMT in a smad protein-dependent mechanism (Wang et al., 2014). All of these findings show that apelin/APJ system can reduce the deposition of ECM and improve renal interstitial fibrosis. Therefore, apelin/APJ system has potential renoprotective effects, which is an effective agent for retarding CKD progression.

3.2 Apelin/APJ system alleviates renal ischemia/reperfusion injury

Renal ischemia/reperfusion (I/R) injury is the leading cause of acute kidney injury (AKI) during surgery, arterial occlusion, shock, and organ transplantation (Yamamoto et al., 2011). Renal I/R can cause tubular epithelial cell damage, including renal tubular obstruction and decreased NaCl resorption. Chen et al. (2015) show that apelin-13 can significantly reduce renal tubular lesions and renal cell death. Apelin-13 inhibits up-regulation of TGF-β1, the level of H3K4me2 and Kmt2d (the histone methyltransferase of H3K4me2) induced by I/R or H/R (hypoxia/reperfusion) injury in glomerular mesangial and tubular cells (Figure 1) (Chen et al., 2015). All of the above results suggest that apelin-13 alleviates acute renal injury. Sagiroglu et al. (2012) also find the intraperitoneal injection of apelin increases the glomerular filtration rate, and decreases the degree of kidney damage in the renal I/R rats. TGF-β1, a major member of the TGF family, is closely associated with the fibrosis of renal disease and inflammation (Choi, Ding, & Kim, 2012). Bircan, Cakir, Kirbag, and Gul, (2016) detail the possible protective effect of apelin-13 on the kidney I/R injury. Results show that apelin-13 treatment can increase serum blood urea nitrogen (BUN), creatinine (CRE), Cl, and tumor necrosis factor alpha (TNF-α) levels, and decrease Na, total protein, albumin, total antioxidant status (TAS) levels. Therefore, the inhibition of TGF-β1 may be related to the protective effect of apelin-13 on renal injury. Besides, apelin-13 increases the antioxidant enzyme activity, prevents the lipid oxidation and improves the renal functions in renal I/R.

3.3 Apelin/APJ system induces or prevents DN

DN is one of the main complications in diabetes, and is also the most common etiology of the end-stage renal disease (Maezawa, Takemoto, & Yokote, 2015). The early clinical manifestations of DN include glomerular hypertrophy and thickening of glomerular basement membrane (Cooper, 2001). With the progress of the disease, high glomerular filtration can lead to proteinuria, eventually developing end-stage renal disease (Susztak & Bottinger, 2006). Studies show that apelin/APJ system plays an important role in the DN. Compared with healthy subject, patients with type 2 diabetes appears to higher serum levels of apelin. And urinary albumin and serum apelin levels are positively correlated. Additionally, apelin increases trace protein in the urine and the ratio of CRE in KK mice (Zhang et al., 2013). Apelin increases the migration, proliferation, and tropism of glomerular endothelial cell in dose dependent. The increasing of apelin promotes the permeability of glomerular endothelial cells, and increases vascular endothelial growth factor and the expression of adenosine diphosphate (Zhang et al., 2013). Some studies also suggest that apelin/APJ system can induce the produce of endothelial cells by an autocrine or paracrine manner (Cox, D'Agostino, Miller, Heimark, & Krieg, 2006). Therefore, the apelin can promote angiogenesis of the glomerulus, forming abnormal blood vessels by adjusting the vascular endothelial growth factor in type 2 diabetes mellitus. Meanwhile, the permeability of glomerular endothelial cells is enhanced through adjusting the vascular endothelial growth factor. And the expression of adenosine diphosphate enhances the permeability of glomerular endothelial cells.

Apelin also plays an important role in regulating DN blood vessel function. The decrease of APJ protein and increase of contractile responding to Ang II and Ang IV are exhibited in renal arteries from db/db mice. But, after apelin supplement, the abnormal renal vascular tone in responses to Ang II and acetylcholine in diabetic mice is reversed. These beneficial effects of apelin are thought to result mainly from activation of eNOS phosphorylation and enhancement of NO generation (Zhong et al., 2007).

Studies show the exogenous apelin can slow the progress of DN. Day, Cavaglieri, and Feliers, (2013) study the mice with type 1 diabetes received daily subcutaneous injections of apelin for 2 or 14 weeks. The study finds that apelin does not affect the diabetic rat's blood glucose, body weight, and blood pressure, but inhibit the whole kidney and glomerular hypertrophy, as well the renal inflammation. And apelin can decrease the expression of monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule 1 (VCAM1), the activation of NF-κB and the infiltration of monocyte (Figure 2) (Day et al., 2013). The above results show that apelin can protect DN. Apelin may be used as a new tool for the treatment of DN. In vivo studies also show that apelin has an effect on the treatment of DN. Silva et al. (2013) find the correlation between different apelin levels and cardiovascular mortality, hospitalization rates, renal function, and cardiovascular risk factors in patients with type 2 diabetes. The study finds that the patients with higher baseline apelin level group have a higher survival in 83 months, apelin level is an independent predictor of death and hospitalization. Apelin levels are negatively correlated with cardiovascular risk factors, but are positively correlated with the levels of estimated glomerular filtration rate (eGFR) (Silva et al., 2013). These results suggest that apelin may be as predictive factors for cardiovascular death and hospitalization, and even can play a role in treatment. What is the mechanism that apelin affects the progression of DN? Chen et al. (2014) find that apelin may inhibit the progress of DN by adjusting the histone acetylation. In spontaneous DN mice model, the tail vein injection of apelin-13 can reduce the glomerular filtration rate, proteinuria, glomerular hypertrophy, and glomerular mesangial expansion, lower histone acetylation and kidney inflammation. Application of apelin-13 in glomerular mesangial cells can not only suppress the height of histone acetylation induced by hyperglycemia and inflammatory factor, but also raise histone deacetylase1 (Chen et al., 2014).

However, some studies believe that apelin may also promote the progress of DN. Podocyte damage is associated with the disease progression of DN. Guo et al. (2015) find that apelin can induces podocyte function disorder through the inhibition of the proteasome activity, in turn, promote the progress of DN disease. Apelin can increases proteinuria in kk-Ay mice and reduces podocyte proteins expression. It is consistent with the increase of glomerular APJ levels in patients with DN and mice. The increased expression of APJ in high glucose cultivate podocyte and injection of apelin-13 in kk-Ay mice celiac causes the foot process protein level decreased and permeability increased. All of these dysfunction is associated with the decrease of 26s proteasome activation and the crease of many ubiquitin proteins in kk-Ay mice and podocytes. Because the apelin can also increase C/EBP homologous protein (CHOP) and the levels of peiFα (phosphorylates eukaryotic translation initiation factor α), so these effects may be associated with ER stress (ERS) (Guo et al., 2015).

Why does this contradiction arise? First of all, the focus of the research is different. The main focus is on ERS and oxidative stress (OS). The interaction mechanism between ERS and OS is not clear. The role of apelin/APJ system in this regard is worthy of further study and attention. Second, DN is a complex process. The role of apelin is associated to many factors of the occurrence and development of DN, such as insulin resistance, obesity, and glycolipid metabolism disorders. Therefore, the role of apelin/APJ system in DN disease progression is controversial, which still needs further research.(Table 1)

3.4 Apelin/APJ system predicts on the progress of polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening genetic disease, promoting the progression of end-stage renal disease and cardiovascular disease (Perrone, Ruthazer, & Terrin, 2001). Polycystic kidney disease is characterized by thickening of the tubular basement membrane, renal interstitial fibrosis, and the formation of renal cysts, resulting in structural changes in the kidneys, and ultimately the formation of end stage renal disease (Grantham, 1996). Some scholars evaluate the correlation between apelin and TGF-β1 and ADPKD. They find that the level of apelin is lower, and the level of TGF-β1 is higher in ADPKD patients. At the same time, apelin is negatively correlated with TGF-β1, and is positively correlated with eGFR (Kocer, Karakukcu, Ozturk, Eroglu, & Kocyigit, 2016). Lacquaniti et al. (2013) also show that apelin level is lower, and the copeptin is higher in 52 patients with ADPKD compared with healthy subjects. Analysis of receiver operating characteristic curve (ROC) find that apelin and copeptin shows good receiver operating characteristic curve, in the process of identifying ADPKD disease (Lacquaniti et al., 2013). Cox proportional hazards regression model also show that apelin can predict on the progress of kidney disease. Compared to the eGFR, apelin may appear to a better role in predicting ADPKD disease process, and provides more information.

3.5 Apelin/APJ system promotes dialysis complications in HD

HD is one of the effective alternative treatment approaches for patients with end-stage renal disease. The concentration of apelin increase in the CKD5 stage patients treated with blood and peritoneal dialysis (Szczepanska et al., 2015). In peritoneal dialysis patients, apelin-36 level has is a negatively correlated with age and left ventricular diameter. The diastolic blood pressure, ejection fraction, total cholesterol, LDL cholesterol, HDL cholesterol, parathyroid hormone, and alkaline phosphatase (ALP) levels are positively correlated with apelin-36 level. The linear analysis results show that the diastolic blood pressure, LDL cholesterol, ALP, and ejection fraction are the independent determinants of apelin-36 (Karadag et al., 2014). Thus, apelin/APJ system plays an important role in capacity adjustment, cardiovascular function, lipid metabolism, and bone mineral disorders in patients with peritoneal dialysis. Mafra et al. (2012) also report that apelin levels and PTH levels are positively correlated in HD patients. Additionally, the level of apelin level is significantly increased in the patients with the PTH > 300 pg/ml compared to the PTH < 300 pg/ml (Mafra et al., 2012), And apelin can protect bone dialysis patients. Leal et al.(2012) find that the apelin-36 level has no difference in HD, but the apelin-12 level is much higher in HD patients. The level of TNF-α, c-reactive protein, and LDL (−) are far higher than that of control group in dialysis patients (Leal et al., 2012). However, apelin-12 and apelin-36 are not associated with inflammation and OS markers. Thus, plasma apelin level seems to be not associated with cardiovascular risk in HD patients. Interestingly, the apelin level is increased in the process of dialysis treatment, but decreased in the plasma osmotic pressure, arginine vasopressin (AVP), and mean blood pressure. Thus, apelin is a negatively correlated with high-sensitivity c-reactive proteins (Cernaro et al., 2012), while AVP/apelin can balance the change of dialysis plasma osmotic pressure in the process of dialysis. Therefore, AVP/apelin can be used as markers for arterial low or high pressure. In the stability of dialysis patients, apelin is associated with echocardiographic parameters, diabetes, coronary artery disease, and chronic heart failure, cardiac function classification, and blood lipid, high-sensitivity c-reactive protein, vascular pseudo willebrand factor, residual kidney function. Multivariate analysis shows that apelin level is significantly associated with ejection fraction, diabetes, arteriovenous fistula position (Malyszko, Kozminski, Malyszko, & Mysliwiec, 2011). Therefore, apelin may be associated with the pathology physiology of cardiovascular disease and chronic heart failure. El-Shehaby, El-Khatib, Battah, and Roshdy, (2010) also find that apelin level in dialysis patients is a positive correlation with left ventricular end systolic diameter, left ventricular end-diastolic diameter, interventricular septum, the right ventricle, the left ventricle, and the aorta, but is negatively correlated with high-sensitivity c-reactive proteins and IL-6 (El-Shehaby et al., 2010).

3.6 The other role of apelin/APJ system in kidney disease

VC is associated with increased risk of cardiovascular events, which are the most common cause of death in patients with CKD (Giachelli, 2004). It is reported that apelin/APJ system can effectively restrain the osteoblast differentiation in the calcification of vascular smooth muscle cells (Yuan et al., 2015). Shan et al. (2011) indicate that apelin inhibits the VC in CKD condition. Additionally, apelin-13 can inhibit calcium deposition by inhibiting osteoblast transforming gene BMP-2, OPG, and Cbfa1 induction in human arterial smooth muscle cells (HASMCs) (Han et al., 2016). These effects are mediated by sodium phosphate coordinated transport protein expression and phosphate intake. In phosphate-induced mineralization of human aortic smooth muscle cells (HASMCs) and in adenine-induced CKD rats with aortic calcification, apelin ameliorates VC by suppressing the osteoblastic differentiation of VSMCs and the downregulation of Pit-1 (Han et al., 2016). These results suggest apelin may have potential therapeutic value for treatment of VC in CKD. Malyszko, Malyszko, Pawlak, Wolczynski, and Mysliwiec, (2008) study the association between apelin and coronary artery disease (CAD) in kidney allograft recipients. These results show that apelin is significantly reduced in kidney allograft recipients with CAD. And apelin level can be predicted by the presence of CAD, endothelial damage, or inflammation. Apelin may be associated with inflammation and its clinical consequences (Malyszko et al., 2008).