Mitochondria Protection after Acute Ischemia Prevents Prolonged Upregulation of IL-1β and IL-18 and Arrests CKD.
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-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 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-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.
['Szeto|Hazel H|HH|', 'Liu|Shaoyi|S|', 'Soong|Yi|Y|', 'Seshan|Surya V|SV|', 'Cohen-Gould|Leona|L|', 'Manichev|Viacheslav|V|', 'Feldman|Leonard C|LC|', 'Gustafsson|Torgny|T|']
D000208:Acute Disease D000818:Animals D020382:Interleukin-18 D053583:Interleukin-1beta D007511:Ischemia D007668:Kidney D008297:Male D008928:Mitochondria D009842:Oligopeptides D050199:Podocytes D051381:Rats D017207:Rats, Sprague-Dawley D051436:Renal Insufficiency, Chronic D013997:Time Factors D015854:Up-Regulation
innate immunity inflammasome Podocytes Elamipretide SS- 31 microvascular rarefaction