The Role of Apelin on the Alleviative Effect of Angiotensin Receptor Blocker in Unilateral Ureteral Obstruction-Induced Renal Fibrosis

Abstract

Background: Apelin is a selective endogenous ligand of the APJ receptor, which genetically has closest identity to the angiotensin II type 1 receptor (AT-1). The effects of the apelin/APJ system on renal fibrosis still remain unclear. Methods: We examined the effects of the apelin/APJ system on renal fibrosis during AT-1 blockade in a mouse unilateral ureteral obstruction (UUO) model. Results: We obtained the following results: (1) At UUO day 7, mRNA expressions of apelin/APJ and phosphorylations of Akt/endothelial nitric oxide synthase (eNOS) in the UUO kidney were increased compared to those in the nonobstructed kidney. (2) AT-1 blockade by the treatment with losartan resulted in a further increase of apelin mRNA as well as phosphorylations of Akt/eNOS proteins, and this was accompanied by alleviated renal interstitial fibrosis, decreased myofibroblast accumulation, and a decreased number of interstitial macrophages. (3) Blockade of the APJ receptor by the treatment with F13A during losartan administration completely abrogated the effects of losartan in the activation of the Akt/eNOS pathway and the amelioration of renal fibrosis. (4) Inhibition of NOS by the treatment with L-NAME also resulted in a further increase in renal fibrosis compared to the control group. Conclusion: These results suggest that increased nitric oxide production through the apelin/APJ/Akt/eNOS pathway may, at least in part, contribute to the alleviative effect of losartan in UUO-induced renal fibrosis.

Pancreatitis activates pancreatic apelin-APJ axis in mice

“…In human liver disease, apelin seems to mediate profibrogenic gene induction promoted by ANG II and endothelin-1 in hepatic stellate cells. In agreement with the findings in the pancreas, apelin exerts antifibrosis activities in the kidney and heart (29,32,45).…”

“…Apelin has inhibitory activity against human immunodeficiency virus infection (3,58), reduces proinflammatory cytokine production in spleen cells (13) and in the mouse cardiovascular system, and lowers abdominal aortic aneurysm formation by reducing disease-associated vascular inflammation (23). Recent reports demonstrate an emerging role for the apelin-APJ axis in regulation of liver, kidney, and heart fibrosis (24,29,32,45).…”

“…Our laboratory (16) reported that intestinal apelin is involved in the inflammatory response of the intestine. Emerging data indicate a role for apelin in regulation of fibrosis in the kidney, heart, and liver (24,29,32,45). Whether the apelin-APJ signaling system is involved in regulation of pancreatic fibrosis during pancreatitis has not been investigated.…”

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

“…Autosomal dominant polycystic kidney disease (ADPKD) patients are characterized by low apelin levels (Lacquaniti et al, ). Nishida et al () find that both apelin and APJ receptor mRNAs are upregulated at day 7 after unilateral ureteral obstruction (UUO). These results indicate that apelin/APJ system is linked to kidney disease, which is likely to predict the progression of certain kidney diseases.…”

Apelin/APJ system: A novel therapeutic target for oxidative stress-related inflammatory diseases (Review)

“…Apelin can also restore the levels of antioxidant enzymes in the kidneys of diabetic mice, reduce oxidative stress, and prevent damage to kidneys from oxidative stress (48). Thus, apelin may be a therapeutic target in DN by exerting anti-oxidantive effects (Fig.…”