Persistent disruption of mitochondrial homeostasis after acute kidney injury

Jason A. Funk, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

147 Scopus citations

Abstract

While mitochondrial dysfunction is a pathological process that occurs after acute kidney injury (AKI), the state of mitochondrial homeostasis during the injury and recovery phases of AKI remains unclear. We examined markers of mitochondrial homeostasis in two nonlethal rodent AKI models. Myoglobinuric AKI was induced by glycerol injection into rats, and mice were subjected to ischemic AKI. Animals in both models had elevated serum creatinine, indicative of renal dysfunction, 24 h after injury which partially recovered over 144 h postinjury. Markers of proximal tubule function/injury, including neutrophil gelatinase-associated li-pocalin and urine glucose, did not recover during this same period. The persistent pathological state was confirmed by sustained caspase 3 cleavage and evidence of tubule dilation and brush-border damage. Respiratory proteins NDUFB8, ATP synthase β, cytochrome c oxidase subunit I (COX I), and COX IV were decreased in both injury models and did not recover by 144 h. Immunohistochemical analysis confirmed that COX IV protein was progressively lost in proximal tubules of the kidney cortex after ischemia-reperfusion (I/R). Expression of mitochondrial fission protein Drp1 was elevated after injury in both models, whereas the fusion protein Mfn2 was elevated after glycerol injury but decreased after I/R AKI. LC3-I/II expression revealed that autophagy increased in both injury models at the later time points. Markers of mitochondrial biogenesis, such as PGC-1α and PRC, were elevated in both models. These findings reveal that there is persistent disruption of mitochondrial homeostasis and sustained tubular damage after AKI, even in the presence of mitochondrial recovery signals and improved glomerular filtration.

Original languageEnglish (US)
Pages (from-to)F853-F864
JournalAmerican Journal of Physiology - Renal Physiology
Volume302
Issue number7
DOIs
StatePublished - Apr 1 2012
Externally publishedYes

Keywords

  • Ischemia
  • Mitochondria
  • Proximal tubules
  • Rhabdomyolysis

ASJC Scopus subject areas

  • Physiology
  • Urology

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