Abstract
Background: Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and a common cause of end-stage renal disease. Autophagy has a defensive role against kidney damage caused by hyperglycemia. Mesenchymal stem cell (MSC)-derived exosomes are currently considered as a new promising therapy for chronic renal injury. However, the renal-protective mechanism of exosomes on DN is not completely understood. We examined the potential role of MSC-derived exosomes for enhancement of autophagy activity and their 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), chloroquine, and exosome groups. We assessed renal function, morphology, and fibrosis. Moreover, ratios of the autophagy markers mechanistic target of rapamycin (mTOR), Beclin-1, light chain-3 (LC3-II), and LC3-II/LC3-I were detected. Additionally, electron microscopy was used for detection of autophagosomes. Results: Exosomes markedly improved renal function and showed histological restoration of renal tissues, with significant increase of LC3 and Beclin-1, and significant decrease of mTOR and fibrotic marker expression in renal tissue. All previous effects were partially abolished by the autophagy inhibitors chloroquine and 3-MA. Conclusion: We conclude that autophagy induction by exosomes could attenuate DN in a rat model of streptozotocin-induced diabetes mellitus.
Highlights
Diabetic nephropathy (DN) is a devastating complication of diabetes mellitus and a leading cause of end-stage renal disease (ESRD) worldwide [1]
The amount of purified exosome was significantly (p < 0.05) increased over the passages, and reached maximum concentration in the third passage, which was used for administration to rats (Figure 2 C,D)
It has been reported that activated mechanistic target of rapamycin (mTOR) enhances interstitial fibrosis in diabetic kidneys [20]. These findings are parallel to those of the present study, as we demonstrated a significant increase in TGF-β1 and fibronectin protein expression (Figure 10), and collagen fiber deposition among the glomerular capillaries and surrounding the renal corpuscles and tubules in renal specimens stained by Masson's trichrome in DN rats, as compared to controls (Figure 5)
Summary
Diabetic nephropathy (DN) is a devastating complication of diabetes mellitus and a leading cause of end-stage renal disease (ESRD) worldwide [1]. Current therapeutic modalities for DN are directed at controlling the diabetes-associated metabolic and hemodynamic changes to slow disease progression, while no therapy exists to repair the imminent renal damage [7]. Over the past decade, mesenchymal stem cells (MSCs) have gained increasing interest as a novel regenerative therapy against renal damage [8]. Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and a common cause of end-stage renal disease. Mesenchymal stem cell (MSC)-derived exosomes are currently considered as a new promising therapy for chronic renal injury. We examined the potential role of MSC-derived exosomes for enhancement of autophagy activity and their effect on DN. Ratios of the autophagy markers mechanistic target of rapamycin (mTOR), Beclin-1, light chain-3
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