2. Academic Validation
  3. Sirtuin 6 is a key contributor to gender differences in acute kidney injury

Sirtuin 6 is a key contributor to gender differences in acute kidney injury

  • Cell Death Discov. 2023 Apr 25;9(1):134. doi: 10.1038/s41420-023-01432-y.
Jinhua Miao # 1,  Jiewu Huang # 1,  Ye Liang # 1,  Yunfang Zhang # 2,  Jiemei Li 1,  Ping Meng 2,  Weiwei Shen 1,  Xiaolong Li 1,  Qinyu Wu 1,  Xiaoxu Wang 1,  Hongxin Niu 3,  Ying Tang 4,  Shan Zhou 5,  Lili Zhou 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Nephrology, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 2 Department of Nephrology, Huadu District People's Hospital, Southern Medical University, Guangzhou, China.
  • 3 Department of General Practice, Special Medical Service Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China. [email protected].
  • 4 Department of Nephrology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. [email protected].
  • 5 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Nephrology, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China. [email protected].
  • 6 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Guangdong Provincial Key Laboratory of Nephrology, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 37185276 DOI: 10.1038/s41420-023-01432-y
Abstract

Acute kidney injury (AKI) is rapidly increasing nowadays and at a high risk to progress into chronic kidney disease (CKD). Of note, men are more susceptive to AKI, suggesting gender differences in AKI patients. However, the underlying mechanisms remain largely unclear. To test it, we adopted two experimental models of AKI, including ischemia/reperfusion injury and rhabdomyolysis, which were constructed in age-matched male and female mice. We found severe damages of tubular Apoptosis, mitochondrial dysfunction, and loss of renal function showing in male mice, while female mice only had very mild injury. We further tested the expression of Sirtuins, and found that female mice could preserve more Sirtuin members' expression in case of kidney damage. Among Sirtuin family, Sirtuin 6 was maximally preserved in injured kidney in female mice, suggesting its important role involved in the gender differences of AKI pathogenesis. We then found that knockdown of Androgen Receptor (AR) attenuated tubular damage, mitochondrial dysfunction and retarded the loss of renal function. Overexpression of Sirtuin 6 also showed similar results. Furthermore, in cultured tubular cells, dihydrotestosterone (DHT) decreased Sirtuin 6 expression and exacerbated cell Apoptosis. Ectopic expression of Sirtuin 6 sufficiently inhibited DHT-induced cell Apoptosis. Mechanically, we found AR inhibited Sirtuin 6, leading to the repression of binding of Sirtuin 6 with PGC-1α. This resulted in acetylation of PGC-1α and inhibition of its activity, further triggered the loss of mitochondrial homeostasis. Our results provided new insights to the underlying mechanisms of gender differences in AKI, suggesting Sirtuin 6 maybe a new therapeutic target for preventing AKI in male patients.

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