Oxidative Stress-Related Mitochondrial and Lysosomal Quality Control Mechanisms in Renal Cortex During the Normoalbuminuric Stage of Diabetes Mellitus

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Background: Oxidative stress during the normoalbuminuric stage of type 1 diabetes mellitus (DM) damages renal cortical mitochondria. Subsequent mitochondrial autophagy (mitophagy) produces autophagosomes destined for lysosomal degradation; hence, any lysosomes damaged in DM must be either repaired or degraded and removed in order for mitophagy to reach fruition. We aimed to determine if oxidative stress in DM triggers not only renal cortical mitophagy, but also lysosomal repair and elimination through lysosome-selective autophagy (lysophagy). Methods: Four groups of rats (n=5 per group) received one of the following treatments: 1) STZ group: rats with DM induced by streptozotocin injection (STZ, 65 mg/kg, i.p.); 2) Sham group: rats receiving the STZ vehicle; 3) STZ+TLM group: STZ rats treated with telmisartan (TLM, an angiotensin receptor blocker; 10 mg/kg/day in chow); and 4) Sham+TLM group: TLM-treated Sham rats. Two weeks later, blood glucose levels, blood pressure, glomerular filtration rate (GFR), and urinary excretion of albumin and N-acetyl-β-D-glucosaminidase (NAG) were measured in each rat. Renal cortex homogenates were assayed for 3-nitrotyrosine (3-NT, an oxidative stress marker measured by HPLC), and Western blot was used to quantify proteins related to mitophagy (PINK1, BNIP3, LC3-II, p62), lysosomal repair (Galectin-3), and lysophagy (LAMP2, FBXO27). Results: Blood glucose levels were higher in STZ rats than in Sham rats (P<0.05) and were unaffected by TLM. Blood pressure, albumin excretion, and NAG excretion were unaltered by STZ or TLM. GFR and renal cortical 3-NT levels were increased in STZ rats (P<0.05), and both changes were prevented by TLM (P<0.05). STZ rats had increased renal cortical LC3-II, PINK1, Galectin-3, and FBXO27 protein levels compared with Sham (P<0.05), with these effects prevented by TLM (P<0.05). BNIP3, p62 and LAMP2 levels did not differ among groups. Conclusions: DM-induced renal cortical mitophagy, lysosomal repair, and lysophagy were blunted by the antioxidant effects of TLM, suggesting that these may be closely related quality control mechanisms triggered by oxidative damage.

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