The ketone body β-hydroxybutyrate mitigates the senescence response of glomerular podocytes to diabetic insults.
The ketone body β-hydroxybutyrate mitigates the senescence response of glomerular podocytes to diabetic insults.
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DOI：
10.1016/j.kint.2021.06.031
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发表时间：
2021-11
影响因子：
19.6
通讯作者：
Gong R
中科院分区：
文献类型：
--
作者：
Fang Y;Chen B;Gong AY;Malhotra DK;Gupta R;Dworkin LD;Gong R
糖尿病肾病(DKD)是糖尿病最常见的并发症之一，其临床特征为进行性蛋白尿，其原因是肾小球破坏，导致足细胞衰老。越来越多的证据表明，酮病，特别是β-羟基丁酸酯，对衰老和无数的代谢或慢性疾病，包括肥胖、糖尿病和慢性肾脏疾病都有有益的影响。它对DKD的影响在很大程度上是未知的。在体外糖尿病环境下的足细胞中，β-羟基丁酸酯处理显著减轻了细胞的衰老和损伤，表现为减少了γH_2AX焦点的形成，减少了衰老相关β-半乳糖苷酶活性的染色，减少了衰老信号的关键调节因子如p16INK4A和p21的表达，并保留了突触素的表达。β-羟丁酸的这种有益作用与增强转录因子NRF2的抗氧化反应相一致。从机制上讲，β-羟丁酸抑制糖原合成酶激酶3β(GSK3β)是调节NRF2活性的无数信号通路的汇聚点，似乎起到了作用。事实上，NRF2的选择性抑制剂胡芦巴碱或成分活性突变体GSK3β的异位表达被取消，而NRF2的选择性激活足以发挥β-羟丁酸酯的抗衰老和足细胞保护作用。此外，分子模拟和对接分析表明，β-羟基丁酸酯能够直接靶向β的三磷酸腺苷结合口袋，从而阻断其激酶活性。在链脲佐菌素诱导的小鼠糖尿病肾病模型中，β-羟丁酸盐治疗抑制肾小球足细胞GSK3β和增强NRF2的激活，从而减轻足细胞的衰老和损伤，改善糖尿病肾小球病变和蛋白尿。因此，我们的发现可能为开发一种基于β-羟丁酸盐的治疗酮病治疗糖尿病肾病的新方法铺平道路。
Diabetic kidney disease (DKD) is one of the most common complications of diabetes and clinically featured by progressive albuminuria, consequent to glomerular destruction that involves podocyte senescence. Burgeoning evidence suggests that ketosis, in particular β-hydroxybutyrate, exerts a beneficial effect on aging and on myriad metabolic or chronic diseases, including obesity, diabetes and chronic kidney diseases. Its effect on DKD is largely unknown. In vitro in podocytes exposed to a diabetic milieu, β-hydroxybutyrate treatment substantially mitigated cellular senescence and injury, as evidenced by reduced formation of γH2AX foci, reduced staining for senescence-associated-β-galactosidase activity, diminished expression of key mediators of senescence signaling like p16INK4A and p21, and preserved expression of synaptopodin. This beneficial action of β-hydroxybutyrate coincided with a reinforced transcription factor Nrf2 antioxidant response. Mechanistically, β-hydroxybutyrate inhibition of glycogen synthase kinase 3β (GSK3β), a convergent point for myriad signaling pathways regulating Nrf2 activity, seems to contribute. Indeed, trigonelline, a selective inhibitor of Nrf2, or ectopic expression of constitutively active mutant GSK3β abolished, whereas selective activation of Nrf2 was sufficient for the anti-senescent and podocyte protective effects of β-hydroxybutyrate. Moreover, molecular modeling and docking analysis revealed that β-hydroxybutyrate is able to directly target the ATP-binding pocket of GSK3β and thereby block its kinase activity. In murine models of streptozotocin-elicited DKD, β-hydroxybutyrate therapy inhibited GSK3β and reinforced Nrf2 activation in glomerular podocytes, resulting in lessened podocyte senescence and injury and improved diabetic glomerulopathy and albuminuria. Thus, our findings may pave the way for developing a β-hydroxybutyrate-based novel approach of therapeutic ketosis for treating DKD.
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