Angiotensin Ii‐induced Hypertension and Glomerular and Tubulointerstitial Injury in Mutant Mice With Kidney Proximal Tubule‐selective Deletion of Mitochondrial Nad+‐dependent Deacetylase Sirtuin 3: Focus on Sex Differences
Authors: Leite Ana Paula O. , Li Xiao C. , Hassan Rumana , Zhuo Jia L. 
Published: May 2022

Sirtuin 3 (SIRT3) is a major mitochondrial NAD‐dependent Deacetylase closely involved in energy production, cell metabolism, oxidative stress responses, and mitochondrial homeostasis during hypertension and kidney diseases. However, it remains unknown whether deletion of SIRT3 in the proximal tubules alters the hypertensive and kidney glomerular and tubulointerstitial fibrotic responses to angiotensin II (Ang II) in sex‐dependent manners. In the present study, adult male and female wild‐type (WT) and mutant mice with proximal tubule‐specific deletion of SIRT3, PT‐Sirt3‐/‐, were infused without (time controls) or with a slow pressor dose of Ang II via an osmotic minipump (0.5 mg/kg/day, i.p.), supplemented with a 2% NaCI diet or losartan, 20 mg/kg/day, for 2 weeks. Systolic (SBP), diastolic (DBP), and mean arterial blood (MAP) pressure were determined using the tail‐cuff method, whereas 24 hr. urinary sodium and potassium excretion were determined using a metabolic cage. Serum and urine creatinine were measured using colorimetric assays, whereas glomerular and tubulointerstitial injury was evaluated by Masson’s Trichrome staining. Basal SBP, DBP, and MAP were significantly lower in PT‐Sirt3‐/‐ mice than WT (WT‐SBP: 112 ± 2 vs. PT‐Sirt3‐/‐‐SBP: 93 ± 2 mmHg, P<0,01). The magnitude of Ang II‐induced hypertension was similar between WT and PT‐Sirt3‐/‐ mice with or without losartan treatment. After the establishment of hypertension, both WT and PT‐Sirt3‐/‐ animals significantly increased urine creatinine levels in both males and females (P<0.05). However, male PT‐Sirt3‐/‐ mice had higher urine creatinine excretion than male WT (WT‐Ang II: 734 ± 59 vs PT‐Sirt3‐/‐‐Ang II: 1155 ± 92, µg/mL, P<0.05), but this sex difference was absent in female WT and PT‐Sirt3‐/‐ mice. In general, females had a lower urinary creatinine excretion (UCr) than males. Losartan treatment decreased urinary creatinine excretion in all groups (P<0.05). Similar responses were observed with plasma creatinine levels (SCr), which were higher in PT‐Sirt3‐/‐mice than in WT mice (P<0.05), but without significant sex differences in response to Ang II infusion or losartan treatment. Losartan significantly increased 24 hr urinary potassium and chloride excretion in Ang II‐infused male and female PT‐Sirt3‐/‐ mice (P<0.01). Finally, Ang II‐infused PT‐Sirt3‐/‐ mice showed significant glomerular and renal cortical tubulointerstitial fibrotic responses, compared with WT (P<0.05), without sex differences. Interestingly, losartan treatment did not show decreased fibrotic responses, instead, showed a tendency to higher collagen deposition than in hypertensive PT‐Sirt3‐/‐ mice. In summary and conclusion, male and female PT‐Sirt3‐/‐ mice have lower basal blood pressure, and Ang II‐induced hypertension and renal fibrotic responses are similar in male and female PT‐Sirt3‐/‐ mice without significant sex differences. Our results suggest that AT1a receptors and SIRT3 play important roles in basal blood pressure homeostasis and Ang II‐induced hypertension and glomerular and tubulointerstitial injury in both male and female mice.