Mitochondrial Deacetylase Sirtuin 3 in the Proximal Tubules of the Kidney Plays a Protective Role Against Angiotensin Ii-Induced Hypertension and Kidney Injury in Mice

Objective: Sirtuin 3 (Sirt3), a major NAD-dependent deacetylase in the mitochondrial matrix, exerts anti-oxidative, anti-inflammation, and cardiovascular effects by counteracting angiotensin II (Ang II)-induced responses in the mitochondria. The present study tested the hypothesis that Sirt3 in the mitochondria of the proximal tubules plays a protective role against angiotensin Ang II-induced hypertension and kidney injury. Design and method: To test the hypothesis, we generated mice with proximal tubule-specific deletion of Sirt3, PT-Sirt3-/-, using the iL-Sglt2-Cre/Sirt3f/f recombination approach. Three groups (n=10 each) of adult male wildtype (WT) and PT-Sirt3-/- mice were infused with Ang II (∼0.5 mg/kg/day, i.p., 2 weeks) or induced with 2 h ischemia and reperfusion (I/R) kidney injury. Results: PT-Sirt3-/- mice developed and grew normally without structural abnormalities in the proximal tubules of the kidney. Basal telemetry blood pressure (WT: 118 ± 3 mmHg vs. PT-Sirt3-/-: 102 ± 5 mmHg, P<0.01) and glomerular filtration rate (WT: 165.3 ± 8.4 μl/min vs. PT-Sirt3-/-: 121.3 ± 5.3 μl/min, P<0.01) were significantly lower. However, 24 h urine (WT: 1.38 ± 0.16 mL/24 h vs. PT-Sirt3-/-: 1.82 ± 0.25 mL/24 h, P<0.01) and urinary sodium excretion were higher in adult male PT-Sirt3-/- mice (WT: 158.0 ± 5.2 μmol/24 h vs. PT-Sirt3-/-: 208.0 ± 5.8 μmol/24 h, P<0.01). Deletion of Sirt3 selectively in the proximal tubules significantly increased renin mRNA expression in PT-Sirt3-/- mice (WT: 1173 ± 141 copies/ng RNA vs. PT-Sirt3-/-: 1741 ± 125 copies/ng RNA, P<0.01), but not HIF-1-alpha, fibronectin, or KIM-1 mRNA in the kidney cortex under basal conditions. In response to Ang II infusion, however, deletion of Sirt3 selectively in the proximal tubules of the kidney significantly augmented the pressor response in PT-Sirt3-/- mice (WT: 27 ± 3 mmHg vs. PT-Sirt3-/-: 38 ± 5 mmHg, P<0.01), and increased HIF-1-alpha, TGF-beta1, fibronectin, or KIM-1 mRNA expression in response to 24-h I/R-induced kidney injury (P<0.01). Conclusions: Our data support the hypothesis that Sirt3 in the mitochondria of the proximal tubules plays an important protective role against Ang II-induced hypertension and I/R-induced kidney injury.