Abstract: FR-PO154

Mitochondria-Targeted Antioxidant Peptide SS-31 Attenuates Renal Tubulointerstitial Injury via Regulating Mitochondrial Dynamics in DN

Session Information

  • Mitochondriacs and More
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Zhang, Hao, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
  • Yang, Shi-kun, The third Xiangya Hospital, Central South University, Changsha, China
  • Wang, Jianwen, The third Xiangya Hospital of Central South University, Changsha, China
Background

Accumulating studies indicate that mitochondrial dysfunction is central to the pathogenesis of DN. We investigate the effects and mechanisms of mitochondria-targeted peptide SS-31 therapy on tubulointerstitial injury in DN.

Methods

40 C57BL/6 mices were randomly divided into control, DN group, STZ+SS-31 group, STZ+ normal saline group. The DN model was induced by injection intraperitoneally with 40mg/kg body weight STZ for four times. SS-31 was intraperitoneally injected to the mice every other day for 24 weeks. Renal lesions and the expression of Drp1, P66Shc, Bcl-2, Bax, Caspase-1, IL-1, FN were detected by HE, Masson staining, TUNEL, DHE, immunohistochemistry and western-blot. In vitro, HK-2 cells were incubated with different concentrations of D-glucose (5, 30mM) or high glucose (30mM) combimed with SS-31(100nM) or Drp1 inhibitor Midivi1 for indicated time (0-72h).The expression of Drp1, P66Shc, Bcl-2, Bax, Caspase-1, IL-1, FN were detected by Western-blot and immunoflurescence. Mitochondrial functional and morphology analysis were carried out by measuring ROS, TMRE,mitochondrial morphology.

Results

Extracellular matrix deposition and apoptosis of tubular cells were found in DN mices,The expressions of Drp1, P66Shc, Bax, Caspase-1, IL-1, FN were increased in the kidney of DN mices, while treatment with SS-31 could partially reverse such abnormalities, in addition, SS-31 treatment could attenuate renal pathological changes,serum creatinine, microalbuminuria, renal ROS and apoptosis levels. On the other side, the tubular mitochondrion of DN mice exhibiting deformations, such as swelling and fragmentation, while SS-31 treatment could reduce mitochondria fragmentation. In vitro, HG induced mitochondrial dysfunction, including altered membrane potential and increased overproduction of mitochondrial superoxide. Furthermore, HG increased the expression of Drp1 and P66Shc, Bax, Caspase-1, IL-1, FN. However, pretreatment with SS-31could partially reverse such abnormalities.Pretreatment with Drp1 inhibitor Midivi1 could also ameliorate HG-induced mitochondrial dysfunction, while SS-31 used in combination with Midivi1 could enhance the effects of antioxidant and anti-apoptosis.

Conclusion

These data indicate that SS-31 ameliorates tubulointerstitial injury via inhibiting mitochondrial fragmentation in DN.