title: Mitochondria Protection after Acute Ischemia Prevents Prolonged Upregulation of IL-1βand IL-18 and Arrests CKD.
abstract: The innate immune system has been implicated in both AKI and CKD. Damaged mitochondria release danger molecules, such as reactive oxygen species, DNA, and cardiolipin, which can cause NLRP3 inflammasome activation and upregulation of IL-18 and IL-1βIt is not known if mitochondrial damage persists long after ischemia to sustain chronic inflammasome activation. We conducted a 9-month study in Sprague-Dawley rats after 45 minutes of bilateral renal ischemia. We detected glomerular and peritubular capillary rarefaction, macrophage infiltration, and fibrosis at 1 month. Transmission electron microscopy revealed mitochondrial degeneration, mitophagy, and deformed foot processes in podocytes. These changes progressed over the study period, with a persistent increase in renal cortical expression of IL-18, IL-1β, and TGF-β, despite a gradual decline in TNF-αexpression and macrophage infiltration. Treatment with a mitoprotective agent (SS-31; elamipretide) for 6 weeks, starting 1 month after ischemia, preserved mitochondrial integrity, ameliorated expression levels of all inflammatory markers, restored glomerular capillaries and podocyte structure, and arrested glomerulosclerosis and interstitial fibrosis. Further, helium ion microscopy vividly demonstrated the restoration of podocyte structure by SS-31. The protection by SS-31 was sustained for ≥6 months after treatment ended, with normalization of IL-18 and IL-1βexpression. These results support a role for mitochondrial damage in inflammasome activation and CKD and suggest mitochondrial protection as a novel therapeutic approach that can arrest the progression of CKD. Notably, SS-31 is effective when given long after AKI and provides persistent protection after termination of drug treatment.
authors.affiliation: Department of Pharmacology, hhszeto@med.cornell.edu.|Research Program in Mitochondrial Therapeutics.
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Szeto
authors.affiliation: Department of Pharmacology.|Research Program in Mitochondrial Therapeutics.
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pharmacology.|Research Program in Mitochondrial Therapeutics.
authors.forename: Yi
authors.initials: Y
authors.lastname: Soong
authors.affiliation: Department of Pathology, and.
authors.forename: Surya V
authors.initials: SV
authors.lastname: Seshan
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, New York; and.
authors.forename: Leona
authors.initials: L
authors.lastname: Cohen-Gould
authors.affiliation: Institute of Advanced Materials, Devices, and Nanotechnology, and.|Institute of Advanced Materials, Devices, and Nanotechnology, and.
authors.forename: Viacheslav
authors.initials: V
authors.lastname: Manichev
authors.affiliation: Institute of Advanced Materials, Devices, and Nanotechnology, and.|Department of Physics and Astronomy, Rutgers University, Piscataway, New Jersey.
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Feldman
authors.affiliation: Institute of Advanced Materials, Devices, and Nanotechnology, and.|Department of Physics and Astronomy, Rutgers University, Piscataway, New Jersey.
authors.forename: Torgny
authors.initials: T
authors.lastname: Gustafsson
mesh_terms: D000208:Acute Disease; D000818:Animals; D020382:Interleukin-18 / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology*; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use*; D050199:Podocytes / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000209:etiology* / Q000517:prevention & control*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D020382:Interleukin-18; D053583:Interleukin-1beta; D009842:Oligopeptides; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide
keywords: Elamipretide; Podocytes; SS- 31; inflammasome; innate immunity; microvascular rarefaction