br Conclusion br Conflict of

Conclusion
Conflict of Interest
Author Contributions
Acknowledgements This work was supported by a research grant (SR/50/AS-14/2012) from the Department of Science and Technology, New Delhi, India to CMC and CSIR Senior Research Fellowship (09/013(0339)/2010-EMR-I) to SB.
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 expression 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 Norfloxacin hydrochloride 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.
Materials and methods
Results
Discussion Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease [15], [16]. The pathogenesis of DKD is not fully understood, and there is no effective treatment. Although previous studies suggested that early lesions of DKD are found in glomeruli [17], [18], recent works have shown that tubulointerstitial lesions play a major role in the pathogenesis of DKD after the initial kidney insults [19]. Adiponectin is an anti-inflammatory factor and has been shown to reduce insulin resistance [20], [21], [22]. A cross-sectional study of Pima Indians with diabetes showed that higher serum adiponectin levels were associated with increased albuminuria and worse renal function [23]. Another study showed that patients with serum adiponectin levels above 4 μg/ml had significantly faster renal disease progression [24]. Interestingly, ARBs also alleviate DKD. These studies suggest that the increases in serum adiponectin levels and activation of AT1 may play a role in the development of kidney disease. These findings reveal the existence of adiponectin resistance. AT1 receptor may contribute to adiponectin resistance by inhibiting AdipoR activation and signaling through heterodimerization.