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Sirtuin 5 regulates proximal tubule fatty acid oxidation to protect against acute kidney injury

ABSTRACT: Acute kidney injury (AKI) is a major health care concern. There are no therapies for the treatment of AKI. The primary site of damage during AKI is the proximal tubule, which are highly metabolically active cells that rely upon fatty acids for energy. Proximal tubules are notably mitochondria- and peroxisomes-rich cell type that mediate fatty acid oxidation (FAO). Sirtuins reverse post-translational lysine acylation and control many biological processes including FAO. Sirtuin1 and sirtuin3 are protective against AKI. However, the role of the mitochondrial Sirtuin5 (Sirt5) during AKI has yet to be determined. We found Sirt5 to be highly expressed in the proximal tubule. At baseline Sirtuin5 knockout (Sirt5-/-) animals had modestly decreased mitochondrial function but significantly increased FAO, which was localized to the peroxisome. While no overt kidney phenotype was observed in SIRT5-/- mice, following ischemia reperfusion injury Sirt5-/- animals had significantly improved kidney function and less tissue damage. This coincided with increased peroxisomal activity in the Sirt5-/- proximal tubules in preference to the mitochondria. Here we have identified a novel mechanism driving protection of kidneys from ischemic injury. If this can be harnessed it may prove to be an effective therapeutic.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Birgit Schilling

PROVIDER: MSV000083439 | MassIVE | Wed Feb 13 16:43:00 GMT 2019

SECONDARY ACCESSION(S): PXD012696

REPOSITORIES: MassIVE

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Project description:Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF. AKI in VHL-KO mice leads to prominent HIF activation in all nephron segments, as well as to reduced serum creatinine, serum urea, tubular necrosis, and apoptosis marker caspase-3 protein. At d1 after rhabdomyolysis, when tubular injury is potentially reversible, HIF mediated protection in AKI is associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal as demonstrated by qPCR, pathway enrichment analysis and immunohistochemistry. Together, our data provide evidence for a HIF-orchestrated multi-level shift towards glycolysis as a major mechanism for protection against acute tubular injury. All experiments were carried out in transgenic mice in which selective renal tubular VHL knockout (VHL-KO) was inducible by doxycycline (Reference: Mathia S, Paliege A, Koesters R, Peters H, Neumayer HH, Bachmann S, Rosenberger C. Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein. Acta Physiol (Oxf). 2013; 207(3):565-76.). Four groups of animals were used: 1) controls: untreated mice; 2) VHL-KO: injected with doxycycline (0.1 mg per 10 g body weight SC), 4 days prior to sacrifice; 3) AKI: rhabdomyolysis; 4) VHL-KO/AKI: doxycycline plus rhabdomyolysis. To induce AKI, 50% glycerol (0.05 ml per 10 g body weight) was injected IM into the left hind limb under isoflurane narcosis. Drinking water was withdrawn between 20 h prior and 24 h after glycerol injection.

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Sirtuin 5 regulates proximal tubule fatty acid oxidation to protect against acute kidney injury

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