In addition unconventional mechanisms of internalization can

In addition, unconventional mechanisms of internalization cannot be ignored. It is generally believed that the conventional homologous internalization of a GPCR depends on the activation of G proteins, since GRK activation requires the pre-activation of G proteins (Fig. 2). Feng et al. demonstrated that a mutant AT1R that can interact with Ang II but fails to activate G proteins can induce AT1R homologous internalization via a G protein activation-independent mechanism involving transactivation of the epidermal growth factor receptor [95]. Therefore, this may be a novel way of promoting AT1R internalization. However, despite accumulating in vitro evidence highlighting the molecular mechanisms behind reduced AT1R, additional in vivo studies are required to further link the specific mechanisms to cardiovascular diseases.
Funding This work was supported by grants from the Major Research plan of the National Natural Science Foundation of China (Grant No. 91539205) and the National Natural Science Foundation of China (Grant No. 81770393) to Huirong Liu, and the National Natural Science Foundation of China (Grant No. 31771267) to Suli Zhang.
Introduction It is generally accepted that receptors, including G protein-coupled receptors (GPCRs), function as dimers or oligomers [1]. Indeed, evidence of homodimers and heterodimers has been found for many receptors over the past two decades. Receptor dimerization often acts as an important posttranslational mechanism to regulate the ligand binding, activation, signal transduction, trafficking, and function of the receptors involved [2], [3], [4], [5]. Altered Apelin-13 of receptors may results in abnormal receptor dimerization, leading to accelerated or sustained stimulation of signaling and pathological processes [6]. In addition to contribution to many pathophysiological processes such as cardiac remodeling, hypertension, fibrosis, inflammation and diabetes, renin-angiotensin aldosterone system (RAAS) also plays a pivotal role in the development of diabetic kidney disease (DKD). Inhibition of RAAS alleviates the symptom, reduces renal-cardiovascular outcomes such as heart attack, stroke and DKD, and eventually improves survival. Thus, drugs such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have become the most effective first line of medications prescribed for diabetic patients complicated with or without hypertension [7], [8]. On the other hand, the expression, signaling and function of adiponectin and the receptor system are often compromised in diabetic patients and animal models [9]. Stimulation of AdipoR with adiponectin or small molecule agonists improves diabetic outcomes [10], [11]. Some reports have shown that adiponectin acts against angiotensin II (AngII)-mediated inflammation and -accelerated atherosclerosis [12], whereas AngII inhibits expression of cardiac AdipoR1 through AT1 receptor/ROS/ERK1/2/c-Myc pathway [13]. However, in diabetic renal tubular epithelial cells where adiponectin and angII receptors are co-expressed how the two systems cross-talk or coordinate, and how the receptors respond in expression, ligand binding, protein-protein interaction, trafficking, signaling and functioning are unclear. Understanding of these mechanistic responses may open up an avenue for development of novel therapeutics. Our preliminary in vitro experiments have detected the co-expression of adiponectin and angII receptors in renal tubular epithelial cells. Receptor dimerization screening with bimolecular fluorescence complementation (BiFC) identified formation of heterodimers between the two system receptors (data not published yet). Here we show for the first time that adiponectin and AngII receptors form increased heterodimers in renal tubular epithelial cells under diabetic high glucose condition, contributing to renal tubular interstitial injury, a critical process leading to DKD.