Influence of age on gender-related differences in acute kidney injury after minimally invasive radical or partial nephrectomy

Kim, Na Young; Lee, Hye Sun; Park, Jin Ha; Jeon, Soyoung; Oh, Cheol Kyu

doi:10.1007/s00464-021-08590-z

Cited by 2 publications

(7 citation statements)

References 22 publications

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“…AKI is at an increased morbidity, mortality and high costs [ 47 ]. Studies have found that gender difference exists in the incidence of AKI [ 4 , 11 ]. The large epidemiologic and retrospective studies showed that female gender is a protective factor for ischemic AKI after non-cardiac surgery and nephrectomy induced-AKI, although this is still controversial [ 4 , 10 , 48 – 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…Nowadays, the incidence of AKI is rapidly increasing worldwide [ 2 , 3 ]. Epidemical investigation showed, regardless of the multiple pathogenesis of AKI involving sepsis, ischemia-reperfusion injury (IRI), or various nephrotoxins [ 1 ], men are more susceptible to suffer from AKI [ 4 , 5 ]. Indeed, the gender differences occur in many diseases such as pulmonary hypertension [ 6 ], autoimmune diseases [ 7 ] and neurodegenerative diseases [ 8 , 9 ], as well as AKI [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, the gender differences occur in many diseases such as pulmonary hypertension [ 6 ], autoimmune diseases [ 7 ] and neurodegenerative diseases [ 8 , 9 ], as well as AKI [ 10 ]. Several reports have shown that sex hormones may play important roles in gender differences in the prevalence of diseases [ 4 , 5 , 11 ]. However, the underlying mechanisms of gender differences in the pathogenesis of AKI have not been clarified in detail.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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“…Previous mouse studies indicated that longer renal pedicle clamp times (30 min or longer), which are designed to induce severe AKI, induce more extensive renal tubular injury than shorter clamp times, which are designed to induce mild-to-moderate AKI ( 33 ). In addition, many critical issues other than the ischemia time following IRI can influence the severity of AKI, such as strain, sex, age, and weight ( 6 , 34 , 35 ). Although longer ischemia times induce more significant pathological changes, they are also associated with higher mortality ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

“…Female animals are less likely to suffer from AKI than males ( 4 ), and estrogen protects renal tubular function after experimental ischemic injury ( 5 ). Male animals, including humans, are more susceptible to IRI-induced kidney injury with worsened renal function than females ( 6 ). Previous studies reported that the mortality rates of male rats and mice were significantly increased in a renal IRI model, and renal function recovery and tissue injury were shown to be sex dependent due to sex hormone production ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Estradiol Ameliorates Acute Kidney Ischemia-Reperfusion Injury by Inhibiting the TGF-βRI-SMAD Pathway

Lian

et al. 2022

Front. Immunol.

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Renal ischemia–reperfusion injury (IRI) is less extensive in females than males in both animals and humans; however, this protection diminishes after menopause, suggesting that estrogen plays a pivotal role in IRI, but the underlying mechanism remains largely unknown. Our study found that 45 min of warm ischemia was sufficient to induce significant pathological changes without causing death in model animals. Compared with male rats, female rats exhibited less extensive apoptosis, kidney injury, and fibrosis; these effects were worsened in ovariectomized (OVX) rats and ameliorated upon estradiol (E2) supplementation. Furthermore, the levels of TGF-βRI, but not TGF-βRII or TGF-β1, were significantly increased in OVX rats, accompanied by phosphorylated SMAD2/3 activation. Interestingly, the alteration trend of the nuclear ERα level was opposite that of TGF-βRI. Furthermore, dual luciferase reporter and chromatin immunoprecipitation assays showed that ERα could bind to the promoter region of TGF-βRI and negatively regulate its mRNA expression. Moreover, an in vitro study using NRK-52E cells showed that ERα knockdown blocked E2-mediated protection, while TGF-βRI knockdown protected cells against hypoxic insult. The findings of this study suggest that renal IRI is closely related to the TGF-βRI-SMAD pathway in females and that E2 exert its protective effect via the ERα-mediated transcriptional inhibition of TGF-βRI expression.

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Influence of age on gender-related differences in acute kidney injury after minimally invasive radical or partial nephrectomy

Cited by 2 publications

References 22 publications

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

Estradiol Ameliorates Acute Kidney Ischemia-Reperfusion Injury by Inhibiting the TGF-βRI-SMAD Pathway

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