Mitochondria Protection after Acute Ischemia Prevents Prolonged Upregulation of IL-1β and IL-18 and Arrests CKD

• DOI: 10.1681/asn.2016070761
• Publication Date: 2016-11-24T03:30:20Z
• Authors: Hazel H. Szeto; Shaoyi Liu; Yi Soong; Surya V. Seshan; Leona Cohen-Gould; Viacheslav Manichev; Leonard C. Feldman; Torgny Gustafsson
• Keywords: Glomerulosclerosis; Mitochondrial ROS

The innate immune system has been implicated in both AKI and CKD. Damaged mitochondria release danger molecules, such as reactive oxygen species, DNA, cardiolipin, which can cause NLRP3 inflammasome activation upregulation of IL-18 IL-1β It is not known if mitochondrial damage persists long after ischemia to sustain chronic activation. We conducted a 9-month study Sprague-Dawley rats 45 minutes bilateral renal ischemia. detected glomerular peritubular capillary rarefaction, macrophage infiltration, fibrosis at 1 month. Transmission electron microscopy revealed degeneration, mitophagy, deformed foot processes podocytes. These changes progressed over the period, with persistent increase cortical expression IL-18, IL-1β, TGF-β, despite gradual decline TNF-α infiltration. Treatment mitoprotective agent (SS-31; elamipretide) for 6 weeks, starting month ischemia, preserved integrity, ameliorated levels all inflammatory markers, restored capillaries podocyte structure, arrested glomerulosclerosis interstitial fibrosis. Further, helium ion vividly demonstrated restoration structure by SS-31. protection SS-31 was sustained ≥6 months treatment ended, normalization expression. results support role CKD suggest novel therapeutic approach that arrest progression Notably, effective when given provides termination drug treatment.