SIRT3 deficiency leads to induction of abnormal glycolysis in diabetic kidney with fibrosis

Srivastava, Swayam Prakash; Li, Jinpeng; Kitada, Munehiro; Fujita, Hiroki; Yamada, Yoshio; Goodwin, Julie E.; Kanasaki, Keizo; Koya, Daisuke

doi:10.1038/s41419-018-1057-0

Cited by 137 publications

(170 citation statements)

References 61 publications

Supporting

Mentioning

167

Contrasting

Order By: Relevance

“…Streptozotocin (STZ) induced diabetic CD-1 mouse is a validated model of diabetic kidney disease [28,29]. It has been shown that DPP-4 protein is found higher in the kidneys of diabetic CD-1 mice as compared to kidneys of non-diabetic mice [11].…”

Section: Inhibition Of Ace Suppresses Dpp-4 and Associated Tgfβ Signamentioning

confidence: 99%

Inhibition of Angiotensin-Converting Enzyme Ameliorates Renal Fibrosis by Mitigating DPP-4 Level and Restoring Antifibrotic MicroRNAs

Srivastava

Goodwin

Kanasaki

et al. 2020

Genes

Self Cite

View full text Add to dashboard Cite

Two class of drugs 1) angiotensin-converting enzyme inhibitors (ACEis) and 2) angiotensin II receptor blockers (ARBs) are well-known conventional drugs that can retard the progression of chronic nephropathies to end-stage renal disease. However, there is a lack of comparative studies on the effects of ACEi versus ARB on renal fibrosis. Here, we observed that ACEi ameliorated renal fibrosis by mitigating DPP-4 and TGFβ signaling, whereas, ARB did not show. Moreover, the combination of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), one of the substrates of ACE, with ACEi slightly enhanced the inhibitory effects of ACEi on DPP-4 and associated-TGFβ signaling. Further, the comprehensive miRome analysis in kidneys of ACEi+AcSDKP (combination) treatment revealed the emergence of miR-29s and miR-let-7s as key antifibrotic players. Treatment of cultured cells with ACEi alone or in combination with AcSDKP prevented the downregulated expression of miR-29s and miR-let-7s induced by TGFβ stimulation. Interestingly, ACEi also restored miR-29 and miR-let-7 family cross-talk in endothelial cells, an effect that is shared by AcSDKP suggesting that AcSDKP may be partially involved in the anti-mesenchymal action of ACEi. The results of the present study promise to advance our understanding of how ACEi regulates antifibrotic microRNAs crosstalk and DPP-4 associated-fibrogenic processes which is a critical event in the development of diabetic kidney disease.

show abstract

Section: Inhibition Of Ace Suppresses Dpp-4 and Associated Tgfβ Signamentioning

confidence: 99%

Inhibition of Angiotensin-Converting Enzyme Ameliorates Renal Fibrosis by Mitigating DPP-4 Level and Restoring Antifibrotic MicroRNAs

Srivastava

Goodwin

Kanasaki

et al. 2020

Genes

Self Cite

View full text Add to dashboard Cite

show abstract

“…Sirtuin 3 (Sirt3) is a member of NAD + -dependent deacetylase; it is a key regulator of the mitochondrial respiratory chain and plays an important role in the pathophysiology of various diseases, such as diabetes and metabolic syndrome, and aging [23]. Existing studies have indicated that overexpression of Sirt3 is able to inhibit fibrosis in a variety of animal disease models [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells Attenuate Diabetic Lung Fibrosis via Adjusting Sirt3-Mediated Stress Responses in Rats

Yang

Zhang

Wang

et al. 2020

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Diabetes affects a variety of organs such as the kidneys, eyes, and liver, and there is increasing evidence that the lung is also one of the target organs of diabetes and imbalance of Sirt3-mediated stress responses such as inflammation, oxidative stress, apoptosis, autophagy, and ER stress may contribute to diabetic lung fibrosis. Although previous studies have reported that mesenchymal stem cells (MSCs) have beneficial effects on various diabetic complications, the effect and mechanisms of MSCs on diabetes-induced lung injury are not clear. In this study, the STZ-induced diabetes model was constructed in rats, and the effect and potential mechanisms of bone marrow MSCs on diabetic lung fibrosis were investigated. The results revealed that fibrotic changes in the lung were successfully induced in the diabetic rats, while MSCs significantly inhibited or even reversed the changes. Specifically, MSCs upregulated the expression levels of Sirt3 and SOD2 and then activated the Nrf2/ARE signaling pathway, thereby controlling MDA, GSH content, and iNOS and NADPH oxidase subunit p22phox expression levels in the lung tissue. Meanwhile, high levels of Sirt3 and SOD2 induced by MSCs reduced the expression levels of IL-1β, TNF-α, ICAM-1, and MMP9 by suppressing the NF-κB/HMGB1/NLRP3/caspase-1 signaling pathway, as well as regulating the expression levels of cleaved caspasese-3, Bax, and Bcl2 by upregulating the expression level of P-Akt, thereby inhibiting the apoptosis of the lung tissue. In addition, MSCs also regulated the expression levels of LC3, P62, BiP, Chop, and PERK, thereby enhancing autophagy and attenuating endoplasmic reticulum stress. Taken together, our results suggest that MSCs effectively attenuate diabetic lung fibrosis via adjusting Sirt3-mediated responses, including inflammation, oxidative stress, apoptosis, autophagy, and endoplasmic reticulum stress, providing a theoretical foundation for further exploration of MSC-based diabetic therapeutics.

show abstract

“…However, little is known about the metabolism of renal epithelial cells (Rowe et al, 2013). TGFβ1 is a well‐known mesenchymal inducer (Grande et al, 2015), suppresses fatty acid oxidation (Kang et al, 2015) and induces glucose metabolism in high‐glucose‐treated cultured renal tubular epithelial cells (TECs) (Srivastava et al, 2018). Renal tubular epithelial cells require high levels of baseline energy consumption and are highly dependent on fatty acid oxidation (Kang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Kidney fibrosis is associated with an increased rate of sirtuin 3 (SIRT3) deficiency‐linked abnormal glucose metabolism and mesenchymal activation (Srivastava et al, 2018). SIRT3 is a major mitochondrial deacetylase that targets several diverse enzymes involved in central metabolism resulting in the activation of many oxidative pathways (Kim et al, 2010; Yin & Cadenas, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…SIRT3 blocks organ fibrosis by controlling TGFβ/smad3 signalling (Bindu et al, 2017; Chen et al, 2015; Sosulski, Gongora, Feghali‐Bostwick, Lasky, & Sanchez, 2017). Moreover, disruption in central metabolism leads to kidney injury (Kang et al, 2015; Poyan Mehr et al, 2018; Srivastava et al, 2018; Tran et al, 2016; Zhou et al, 2019). We have observed that SIRT3 deficiency leads to induction of abnormal glucose metabolism through higher pyruvate kinase M2 type (PKM2) dimer formation and hypoxia‐inducible factor‐1α (HIF1α) accumulation (Srivastava et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Metabolic reprogramming by N‐acetyl‐seryl‐aspartyl‐lysyl‐proline protects against diabetic kidney disease

Srivastava

Goodwin

Kanasaki

et al. 2020

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

Background and Purpose ACE inhibitors (ACEIs) and AT1 receptor antagonists (ARBs) are first‐line drugs that are believed to reduce the progression of end‐stage renal disease in diabetic patients. Differences in the effects of ACEIs and ARBs are not well studied and the mechanisms responsible are not well understood. Experimental Approach Male diabetic CD‐1 mice were treated with ACEI, ARB, N‐acetyl‐seryl‐aspartyl‐lysyl‐proline (AcSDKP), ACEI + AcSDKP, ARB + AcSDKP, glycolysis inhibitors or non‐treatment. Moreover, prolyl oligopeptidase inhibitor (POPi)‐injected male diabetic C57Bl6 mice were treated with ACEI, AcSDKP and ARB or non‐treatment. Western blot and immunofluorescent staining were used to examine key enzymes and regulators of central metabolism. Key Results The antifibrotic action of ACEI imidapril is due to an AcSDKP‐mediated antifibrotic mechanism, which reprograms the central metabolism including restoring SIRT3 protein and mitochondrial fatty acid oxidation and suppression of abnormal glucose metabolism in the diabetic kidney. Moreover, the POPi S17092 significantly blocked the AcSDKP synthesis, accelerated kidney fibrosis and disrupted the central metabolism. ACEI partly restored the kidney fibrosis and elevated the AcSDKP level, whereas the ARB (TA‐606) did not show such effects in the POPi‐injected mice. ACE inhibition and AcSDKP suppressed defective metabolism‐linked mesenchymal transformations and reduced collagen‐I and fibronectin accumulation in the diabetic kidneys. Conclusion and Implications The study envisages that AcSDKP is the endogenous antifibrotic mediator that controls the metabolic switch between glucose and fatty acid metabolism and that suppression of AcSDKP leads to disruption of kidney cell metabolism and activates mesenchymal transformations leading to severe fibrosis in the diabetic kidney.

show abstract

SIRT3 deficiency leads to induction of abnormal glycolysis in diabetic kidney with fibrosis

Cited by 137 publications

References 61 publications

Inhibition of Angiotensin-Converting Enzyme Ameliorates Renal Fibrosis by Mitigating DPP-4 Level and Restoring Antifibrotic MicroRNAs

Inhibition of Angiotensin-Converting Enzyme Ameliorates Renal Fibrosis by Mitigating DPP-4 Level and Restoring Antifibrotic MicroRNAs

Mesenchymal Stem Cells Attenuate Diabetic Lung Fibrosis via Adjusting Sirt3-Mediated Stress Responses in Rats

Metabolic reprogramming by N‐acetyl‐seryl‐aspartyl‐lysyl‐proline protects against diabetic kidney disease

Contact Info

Product

Resources

About