Diabetic nephropathy,autophagy and proximal tubule protein endocytic transport:A potentially harmful relationship

Diabetic nephropathy(DN)is the most frequent cause of chronic renal failure.Until now,the pathophysiological mechanisms that determine its development and progression have not yet been elucidated.In the present study,we evaluate the role of autophagy at early stages of DN,induced in type 2 diabetes mellitus(T2DM)mouse,and its association with proximal tubule membrane endocytic receptors,megalin and cubilin.In T2DM animals we observed a tubule-interstitial injury with significantly increased levels of urinary GGT and ALP,but an absence of tubulointerstitial fibrosis.Kidney proximal tubule cells of T2DM animals showed autophagic vesicles larger than those observed in the control group,and an increase in the number of these vesicles marked with LBPA by immunofluorescence.Furthermore,a significant decrease in the ratio of LC3II/LC3I isoforms and in p62 protein expression in DN affected animals is shown.Finally,we observed a marked increase in urinary albumin and vitamin D binding-protein levels in T2DM animals as well as a significant decrease in expression of megalin in the renal cortex.These results indicate an alteration of the tubular endocytic transporters in DN,which could be related to autophagic dysfunction,which would in turn result in impaired organelle recycling,thus contributing to the progression of this disease.

Tubulointerstitial injury and proximal tubule albumin transport in early diabetic nephropathy induced by type 1 diabetes mellitus

A decrease in the tubular expression of albumin endocytic transporters megalin and cubilin has been associated with diabetic nephropathy,but there are no comprehensive studies to date relating early tubulointerstitial injury and the effect of the disease on both transporters in type 1 diabetes mellitus(T1DM).We used eight-week-old male C57BL/6 mice divided into two groups;one of them received the vehicle(control group),while the other received the vehicle+200 mg/kg streptozotocin(T1DM).Ten weeks after the injection,we evaluated plasma insulin,enzymuria,urinary vitamin D-binding protein(VDBP),tubulointerstitial fibrosis and proximal tubule histology,markers of autophagy,and megalin and cubilin levels.We found a reduction in tubular protein reabsorption(albumin and VDBP as specific substances carried by both transporters)with increased tubulointerstitial injury,development of fibrosis,thickening of tubular basement membrane,and an increase in tubular cell metalloproteases.This was associated with a decrease in the renal expression of megalin and cubilin.We also observed an increase in the amount of cellular vesicles of the phagocytic system in the tubules,which could be linked to an alteration of normal intracellular trafficking of both receptors,thus affecting the normal function of transporters in early stages of diabetic nephropathy.In diabetic animals,the added effects of tubulointerstitial injury,the decreases in megalin and cubilin expression,and an altered intracellular trafficking of these receptors,seriously affect protein reabsorption.