Abstract
Despite the recent attention focused on the important role of autophagy in maintaining podocyte homeostasis, little is known about the changes and mechanisms of autophagy in podocyte dysfunction under diabetic condition. In this study, we investigated the role of autophagy in podocyte biology and its involvement in the pathogenesis of diabetic nephropathy. Podocytes had a high basal level of autophagy. And basal autophagy inhibition either by 3-methyladenenine (3-MA) or by Beclin-1 siRNA was detrimental to its architectural structure. However, under diabetic condition in vivo and under high glucose conditions in vitro, high basal level of autophagy in podocytes became defective and defective autophagy facilitated the podocyte injury. Since the dynamics of endoplasmic reticulum(ER) seemed to play a vital role in regulating the autophagic flux, the results that Salubrinal/Tauroursodeoxycholic acid (TUDCA) could restore defective autophagy further indicated that the evolution of autophagy may be mediated by the changes of cytoprotective output in the ER stress. Finally, we demonstrated in vivo that the autophagy of podocyte was inhibited under diabetic status and TUDCA could improve defective autophagy. Taken together, these data suggested that autophagy might be interrupted due to the failure of ER cytoprotective capacity upon high glucose induced unmitigated stress, and the defective autophagy might accelerate the irreparable progression of diabetic nephropathy.
Highlights
Diabetic nephropathy (DN) has become the most common cause of chronic kidney diseases (CKD) that progress to end-stage renal disease (ESRD) in many industrialized countries
Basal autophagy plays an essential role in maintaining podocyte biology and function To explore the significance of autophagy in the kidney diseases, we first investigated the distribution of autophagosomes in normal renal tissue by staining with anti-LC3 antibody
We found that 3-MA treatment could result in a greatly increased amount of albumin influx across the podocyte monolayer compared with the controls (Figure 2, F and G)
Summary
Diabetic nephropathy (DN) has become the most common cause of chronic kidney diseases (CKD) that progress to end-stage renal disease (ESRD) in many industrialized countries. The most common clinical feature of diabetic nephropathy is progressive proteinuria due to compromised glomerular filtration barrier. The morphologically intricate podocyte and its slit diaphragm structure are of primary importance to the integrity of glomerular filtration barrier [1]. Podocytes, derived from embryonic precursor mesenchymal cells, are considered terminally differentiated cells in the mature kidney [3]. The ability to maintain homeostasis under certain pathophysiological stress seems to be very important in determining the fate of podocytes. Finding better therapeutic targets to prevent podocyte injury in diabetic nephropathy has been a great challenge in understanding the modulating mechanisms of podocyte homeostasis
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