Autophagy Inhibits the Accumulation of Advanced Glycation End Products by Promoting Lysosomal Biogenesis and Function in the Kidney Proximal Tubules

Abstract

Advanced glycation end products (AGEs) are involved in the progression of diabetic nephropathy. AGEs filtered by glomeruli or delivered from the circulation are endocytosed and degraded in the lysosomes of kidney proximal tubular epithelial cells (PTECs). Autophagy is a highly conserved degradation system that regulates intracellular homeostasis by engulfing cytoplasmic components. We have recently demonstrated that autophagic degradation of damaged lysosomes is indispensable for cellular homeostasis in some settings. In this study, we tested the hypothesis that autophagy could contribute to the degradation of AGEs in the diabetic kidney by modulating lysosomal biogenesis. Both a high-glucose and exogenous AGE overload gradually blunted autophagic flux in the cultured PTECs. AGE overload upregulated lysosomal biogenesis and function in vitro, which was inhibited in autophagy-deficient PTECs because of the impaired nuclear translocation of transcription factor EB. Consistently, streptozotocin-treated, PTEC-specific, autophagy-deficient mice failed to upregulate lysosomal biogenesis and exhibited the accumulation of AGEs in the glomeruli and renal vasculature as well as in the PTECs, along with worsened inflammation and fibrosis. These results indicate that autophagy contributes to the degradation of AGEs by the upregulation of lysosomal biogenesis and function in diabetic nephropathy. Strategies aimed at promoting lysosomal function hold promise for treating diabetic nephropathy.

Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia

“…Indeed, autophagy is inhibited in kidneys of STZ-induced diabetic rodents [52–54], and impaired autophagy is observed in kidney samples of T2D patients [55]. On the other hand, enhanced autophagy is observed in diabetic mice [56] and proximal tubule epithelial cells cultured in high glucose [57]. While additional studies are needed to delineate regulation of autophagy by sEH and its contribution to DN, it is likely that the enhanced autophagy upon sEH podocyte deficiency in vivo or pharmacological inhibition in culture constituted a protective mechanism against hyperglycemia-induced podocyte injury.…”

SGLT2 Inhibitors Produce Cardiorenal Benefits by Promoting Adaptive Cellular Reprogramming to Induce a State of Fasting Mimicry: A Paradigm Shift in Understanding Their Mechanism of Action

“…Specifically, a deficiency of SIRT1/AMPK activation and impaired autophagy appears to promote the development of cardiomyocyte dysfunction as well as inflammatory processes in diabetic hearts (20,24). In parallel, suppression of SIRT1/AMPK signaling and autophagy has been evoked to explain the pathogenesis of the glomerular and tubular lesions in diabetic nephropathy, particularly the podocyte injury that can lead to proteinuria and the derangements of proximal and distal tubular function that have been linked to advanced glycation end products (21,22,25).…”

DAF in diabetic patients is subject to glycation/inactivation at its active site residues

“…In some samples, the DAF immuno-isolate exhibited faint high Mr (~140 kDa) bands (not shown) in addition to the normal Mr (70 kDa) DAF band. The high molecular weight band approximated the size of “DAF-2,” a previously identified but uncharacterized dimeric form of DAF (Takahashi et al, 2017; Iannuzzi et al, 2016). Precise quantitation of erythrocyte DAF levels in the diabetic samples was not done because the AGE modifications of DAF could impair the binding of anti-DAF Abs.…”

“…The 0.5 M concentration of the sugars although not physiologic was used by us as by others (Takahashi et al, 2017; Iannuzzi et al, 2016) to accelerate the nonenzymatic glycation process which proceeds at a slow pace in vivo. Incubations were carried out in 145 mM NaCl, pH 7.4, 0.1% NP40 in a 1.5 ml Eppendorf tube with gentle rocking.…”