Reduced Autophagy by a microRNA-mediated Signaling Cascade in Diabetes-induced Renal Glomerular Hypertrophy.

ABSTRACT

Autophagy plays a key role in the pathogenesis of kidney diseases, however its role in diabetic nephropathy (DN), and particularly in kidney glomerular mesangial cells (MCs) is not very clear. Transforming Growth Factor- ß1 (TGF-ß), a key player in the pathogenesis of DN, regulates expression of various microRNAs (miRNAs), some of which are known to regulate the expression of autophagy genes. Here we demonstrate that miR-192, induced by TGF-ß signaling, plays an important role in regulating autophagy in DN. The expression of key autophagy genes was decreased in kidneys of streptozotocin-injected type-1 and type-2 (db/db) diabetic mice and this was reversed by treatment with Locked Nucleic Acid (LNA) modified miR-192 inhibitors. Changes in autophagy gene expression were also attenuated in kidneys of diabetic miR-192-KO mice. In vitro studies using mouse glomerular mesangial cells (MMCs) also showed a decrease in autophagy gene expression with TGF-ß treatment. miR-192 mimic oligonucleotides also decreased the expression of certain autophagy genes. These results demonstrate that TGF-ß and miR-192 decrease autophagy in MMCs under diabetic conditions and this can be reversed by inhibition or deletion of miR-192, further supporting miR-192 as a useful therapeutic target for DN.