Abstract
The bioactive peptides of the apelinergic system and its receptor APJ have been shown to play a protective role in experimental cardiovascular and diabetic kidney disease (DKD). Mechanisms of this renoprotective effect remain to be elucidated. In this study, we examined the localization of APJ within the normal kidney and its kidney expression in the db/db model of DKD. The effect of hyperglycemia and angiotensin II on APJ was examined in cultured podocytes. In the glomerulus, APJ colocalized with podocyte but not endothelial cell markers. In podocytes stimulated with Pyr 1Apelin‐13, a change in the phosphorylation status of the signaling proteins, AKT, ERK, and p70S6K, was observed with an increase 15 min after stimulation. Apelin‐13 decreased activity of Caspase‐3 in podocytes after high glucose treatment reflecting an antiapoptotic effect of APJ stimulation. In podocytes, APJ mRNA was downregulated in high glucose, when compared to normal glucose conditions and exposure to angiotensin II led to a further significant decrease in APJ mRNA. APJ and preproapelin mRNA levels in kidneys from db/db mice were markedly decreased along with decreased tubular APJ protein by western blotting and immunostaining when compared to db/m controls. In conclusion, the apelinergic system is decreased in kidneys from db/db mice. Within the glomerulus, APJ is mainly localized in podocytes and in this cell type its activation by Apelin‐13 abolishes the proapoptotic effect of high glucose, suggesting a potential therapeutic role of apelin and emerging agonists with extended half‐life for therapy of DKD.
Highlights
APJ is a G protein-coupled receptor consisting of seven transmembrane domains, that shares a 31% identical amino acid sequence with angiotensin AT1 receptor, but does not bind angiotensin II (Ang II) (Huang et al 2018)
The Messenger RNA (mRNA) levels are reported in relation to those observed in heart tissue where expression of the APJ receptor and preproapelin are known to be abundant (Medhurst et al, 2003)
Under the higher glucose concentration addition of Apelin-13 markedly decreased Caspase-3 activity (14655 Æ 3517 vs. 21722 Æ 5142 RFU/lg, P < 0.05, n = 7). These findings show that in cultured podocytes grown in high glucose conditions, stimulation of APJ by Apelin-13 reduces the proapoptotic effect of excessive glucose
Summary
APJ is a G protein-coupled receptor consisting of seven transmembrane domains, that shares a 31% identical amino acid sequence with angiotensin AT1 receptor, but does not bind angiotensin II (Ang II) (Huang et al 2018). Messenger RNA (mRNA) molecules for preproapelin and APJ are expressed in human tissues such as stomach, brain, heart, kidney, adipose tissue, lung, and in human endothelial cells (Hosoya et al 2000; O’Carroll et al 2000; Medhurst et al 2003; Kleinz and Davenport 2004; Kleinz et al 2005). Both Apelin and APJ are present in cardiac myocytes and vascular smooth muscle cells (Kleinz and Davenport 2004; Hashimoto et al 2006). The therapeutic potential of apelins in cardiovascular disease and preeclampsia is a topic of great interest (Kalea and Batlle 2010; Yamaleyeva et al 2015, 2016; Zhe et al 2016). Of interest is a recent report that has shown that aging promotes and it is later characterized by a state of multiorgan apelinergic deficiency (Rai et al 2017)
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