Mitochondria protection after acute ischemia prevents prolonged upregulation of IL-1b and IL-18 and arrests CKD

Hazel H. Szeto, Shaoyi Liu, Yi Soong, Surya V. Seshan, Leona Cohen-Gould, Viacheslav Manichev, Leonard C. Feldman, Torgny Gustafsson

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

The innate immune systemhas been implicated in both AKI and CKD. Damagedmitochondria release danger molecules, such as reactive oxygen species, DNA, and cardiolipin, which can cause NLRP3 inflammasome activation and upregulation of IL-18 and IL-1β. It 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-α expression and macrophage infiltration. Treatment with a mitoprotective agent (SS-31; elamipretide) for 6 weeks, starting 1month after ischemia, preservedmitochondrial integrity, ameliorated expression levels of all inflammatory markers, restored glomerular capillaries and podocyte structure, and arrested glomerulosclerosis and interstitial fibrosis. Further, heliumion 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-1β expression. 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.

Original languageEnglish
Pages (from-to)1437-1449
Number of pages13
JournalJournal of the American Society of Nephrology
Volume28
Issue number5
DOIs
Publication statusPublished - May 2017

ASJC Scopus subject areas

  • Nephrology

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