Mesenchymal Stem Cell-Derived Exosomes Ameliorated Diabetic Nephropathy by Autophagy Induction through mTOR Signaling Pathway

Abstract

Background: diabetic nephropathy (DN) is a serious complication of diabetes mellitus and a common cause for end stage renal disease. Autophagy has a defensive role against kidney damage caused by hyperglycemia. The mesenchymal stem cells (MSCs) derived exosomes are currently considered as a new promising therapy in chronic renal injury. However, the renal protective mechanism of exosomes on DN has not been completely understood. We examined the potential role of MSCs derived exosomes in enhancement of autophagy activity and its effect on DN. In our study we used five groups of rats; control, DN, DN treated with exosomes, DN treated with 3-methyladenine (3-MA) and chloroquine (inhibitors of autophagy) and DN treated with 3-methyladenine (3-MA) and chloroquine and exosomes groups. We assessed renal functions, morphology and fibrosis. Moreover, autophagy markers; mTOR, Beclin-1, light chain-3 (LC3-II), and LC3-II/LC3-I ratio were detected. Additionally, electron microscopy was used for detection of autophagosomes. Results: Exosomes markedly improved the renal functions and showed histological restoration of renal tissues with significant increase in LC3 and Beclin-1 besides the significant decrease in mTOR and fibrotic markers expression in renal tissue. All previous effects were partially abolished by the autophagy inhibitor, chloroquine and 3-MA. Conclusions: we conclude that autophagy induction by exosomes could attenuate DN in a rat model of streptozotocin-induced diabetes mellitus.

Mesenchymal stem cells and extracellular vesicles in therapy against kidney diseases

“…Autophagy has also been recently considered as a mechanism to delay DN. Ebrahim et al confirmed that MSC-Exos enhance autophagy and then slow the progression of DN via the mTOR signalling pathway [88]. Jin et al further showed that the ADMSC-Exo can inhibit the Smad1/ mTOR signalling pathway by miRNA-486, which promotes autophagy and inhibits apoptosis in podocytes, thus ameliorating the symptoms of DN [89].…”

Importance of extracellular vesicles in hypertension

“…Autophagy induced by EVs also plays a role in cell survival. MSC-derived EVs increase the expression of the autophagy marker LC3 and beclin-1 but decrease the expression of mTOR and fibrotic marker expression in renal tissue, mechanisms that are involved in the improvement renal function and histology of streptozotocin-induced diabetic nephropathy in rats 57. However, the ability of EVs to promote cell survival is not beneficial in cancer because the release of EVs may support tumor cell survival by reducing the chemotherapeutic drug concentration within the tumor cell.…”

Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells

“…The molecular mechanism underlying the induction of autophagy in cancer has not been completely described, but so far, more than 30 autophagy-related genes (ATGs) have been identified (Zhang et al, 2017). Upstream of the ATGs, mammalian target of rapamycin (mTOR) kinase has the most potent impact on autophagy (Ebrahim et al, 2018). mTOR complex 1 (mTORC1) promotes protein synthesis, lipid biogenesis, cell growth, and anabolism and inhibits cellular catabolism by preventing autophagy.…”