Novel roles of mitochondrial deacetylase sirtuin 3 in the proximal tubule in angiotensin II-induced hypertension and ischemia and reperfusion-induced kidney Injury

Abstract

We have recently demonstrated two functional angiotensin II (Ang II)/ Agtr1a/O2- and Ang II/ Agtr2/NO/cGMP signaling pathways in the mitochondria of the proximal tubules of the kidney. Sirtuin 3 (Sirt3) is a major NAD-dependent deacetylase in the mitochondrial matrix, which exerts anti-oxidative, anti-aging, anti-inflammation, and blood pressure-modulating effects in part by counteracting Ang II-increased reactive oxygen species and superoxide production in the mitochondria. In the present study, we hypothesized that Sirt3 in the mitochondria of the proximal tubules plays a key role in protecting against Ang II-induced hypertensive and ischemia and reperfusion (I/R)-induced kidney injury. To test the hypothesis, a mutant mouse model with proximal tubule-specific deletion of Sirt3, PT- Sirt3-/-, was generated using the iL-Sglt2-Cre/ Sirt3f/f recombination approach. Compared with age-matched adult male wildtype mice (WT), basal telemetry blood pressure (WT: 119 ± 3 mmHg vs. PT- Sirt3-/-: 103 ± 5 mmHg, P<0.01) and glomerular filtration rate (WT: 161.7 ± 10.4 μl/min vs. PT- Sirt3-/-: 123.1 ± 7.3 μl/min, P<0.01) were significantly lower, whereas 24 h urine (WT: 1.36 ± 0.23 mL/24 h vs. PT- Sirt3-/-: 1.86 ± 0.30 mL/24 h, P<0.01) and urinary sodium excretion were higher in adult male PT- Sirt3-/- mice (WT: 168.0 ± 5.8 μmol/24 h vs. PT- Sirt3-/-: 218.0 ± 7.9 μmol/24 h, P<0.01). Deletion of Sirt3 selectively in the proximal tubules significantly increased renin mRNA expression in PT- Sirt3-/- mice under basal conditions (WT: 1173 ± 141 copies/ng RNA vs. PT- Sirt3-/-: 1741 ± 125 copies/ng RNA, P<0.01), without altering the expression of angiotensinogen, ACE, ACE2, AT1b or AT2 receptor, as well as HIF-1α, TGF-β1 fibronectin, or KIM-1 mRNAs in the kidney cortex. However, deletion of Sirt3 selectively in the proximal tubules of the kidney significantly increased the pressor response to Ang II infusion (0.5 mg/kg/day, i.p., 2 weeks) in PT- Sirt3-/- mice (WT: Δ27 ± 3 mmHg vs. PT- Sirt3-/-: Δ38 ± 5 mmHg, P<0.01), and HIF-1α, TGF-β1, fibronectin, or KIM-1 mRNA expression in response to the induction of 24-h or 7-day I/R-induced kidney injury ( P<0.01). Masson’s Trichrome staining confirmed that glomerular and tubulointerstitial fibrotic responses were more severe in PT- Sirt3-/- mice than in WT mice in response to Ang II-induced hypertension and kidney I/R ( P<0.01). In conclusion, the results of the present study suggest 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. R01DK123144; R01DK067299; R01DK102429 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.