Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus. It is the most frequent cause of end-stage renal disease with no definitive therapy available so far. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are nano-and micron-sized heterogeneous vesicles that can be secreted by almost all cell types. Importantly, EVs contain many biologically active materials, such as RNAs, DNAs, proteins, and lipids, from their parental cells, which can be transported to their recipient cells to mediate intercellular communication and signaling. Accumulating studies demonstrated that EVs, mainly exosomes and microvesicles, participated in the pathophysiological process of DN. Recently emerging studies also found that the contents of EVs in the urine (miRNAs, mRNAs, and proteins) could be used as potential biomarkers for DN. Therefore, in this mini-review, the generation, isolation methods, and biological function of EVs were introduced, and then the current information about the mechanism and the diagnostic value in the development of DN was summarized. Moreover, the review also discussed the future challenges of exploring the role of EVs in kidney disease.

Diabetic nephropathy (DN) is one of the most serious chronic kidney diseases and the major cause of end-stage renal failure worldwide. The underlying mechanisms of DN are complex and required to be further investigated. Both innate immunity and renin-angiotensin system (RAS) play critical roles in the pathogenesis of DN. Except for traditional functions, abnormally regulated RAS has been proved to be involved in the inflammatory process of DN. Toll-like receptor 4 (TLR4) is the most deeply studied pattern recognition receptor in the innate immune system, and its activation has been reported to mediate the development of DN. In this review, we aim at discussing how dysregulated RAS affects TLR4 activation in the kidney that contributes to the exploration of the pathogenesis of DN. Understanding the interplay of RAS and TLR4 in inducing the progression of DN may provide new insights to develop effective treatments.

Intracellular Ca 2+ overload, prolongation of the action potential duration (APD), and downregulation of inward rectifier potassium (I K1 ) channel are hallmarks of electrical remodeling in cardiac hypertrophy and heart failure (HF). We hypothesized that enhancement of I K1 currents is a compensation for I K1 deficit and a novel modulation for cardiac Ca 2+ homeostasis and pathological remodeling. In adult Sprague-Dawley (SD) rats in vivo , cardiac hypertrophy was induced by isoproterenol (Iso) injection (i.p., 3 mg/kg/d) for 3, 10, and 30 days. Neonatal rat ventricular myocytes (NRVMs) were isolated from 1 to 3 days SD rat pups and treated with 1 μmol/L Iso for 24 h in vitro . The effects of zacopride, a selective I K1 /Kir2.1 channel agonist, on cardiac remodeling/hypertrophy were observed in the settings of 15 μg/kg in vivo and 1 μmol/L in vitro . After exposing to Iso for 3 days and 10 days, rat hearts showed distinct concentric hypertrophy and fibrosis and enhanced pumping function ( P < 0.01 or P < 0.05), then progressed to dilatation and dysfunction post 30 days. Compared with the age-matched control, cardiomyocytes exhibited higher cytosolic Ca 2+ ( P < 0.01 or P < 0.05) and lower SR Ca 2+ content ( P < 0.01 or P < 0.05) all through 3, 10, and 30 days of Iso infusion. The expressions of Kir2.1 and SERCA2 were downregulated, while p -CaMKII, p -RyR2, and cleaved caspase-3 were upregulated. Iso-induced electrophysiological abnormalities were also manifested with resting potential (RP) depolarization ( P < 0.01), APD prolongation ( P < 0.01) in adult cardiomyocytes, and calcium overload in cultured NRVMs ( P < 0.01). Zacopride treatment effectively retarded myocardial hypertrophy and fibrosis, preserved the expression of Kir2.1 and some key players in Ca 2+ homeostasis, normalized the RP ( P < 0.05), and abbreviated APD ( P < 0.01), thus lowered cytosolic [Ca 2 + ] i ( P < 0.01 or P < 0.05). I K1 channel blocker BaCl 2 or chloroquine largely reversed the cardioprotection of zacopride. We conclude that cardiac electrical remodeling is concurrent with structural remodeling. By enhancing cardiac I K1 , zacopride prevents Iso-induced electrical remodeling around intracellular Ca 2+ overload, thereby attenuates cardiac structural disorder a...