Mitochondria and Renal Fibrosis

Quadri, Mohammed; Fatima, Syeda-Safoorah; Che, Ruochen; Zhang, Aihua

doi:10.1007/978-981-13-8871-2_25

Cited by 21 publications

(16 citation statements)

References 43 publications

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“…TGF-β1 is involved in the pro-fibrogenic process after acute or chronic kidney injury. On the one hand, increases in TGF-β1 in various renal cells directly or indirectly leads to mitochondrial dysfunction [35,36]. Excessive mitochondrial fission or decreased fusion may be related to mitochondrial dysfunction and cellular derangement [37].…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 3 Activation by Honokiol Decreases Unilateral Ureteral Obstruction-Induced Renal Inflammation and Fibrosis via Regulation of Mitochondrial Dynamics and the Renal NF-κB-TGF-β1/Smad Signaling Pathway

Quan

Park

Jin

et al. 2020

IJMS

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Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirtuin 3 (SIRT3) is one of the mitochondrial sirtuins, and plays a role in the regulation of mitochondrial biogenesis, oxidative stress, fatty acid metabolism, and aging. Recently, honokiol (HKL), as a pharmaceutical SIRT3 activator, has been observed to have a protective effect against pressure overload-induced cardiac hypertrophy by increasing SIRT3 activity. In this study, we investigated whether HKL, as a SIRT3 activator, also has protective effects against unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis through SIRT3-dependent regulation of mitochondrial dynamics and the nuclear factor-κB (NF-κB)/transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. We found that HKL decreased the UUO-induced increase in tubular injury and extracellular matrix (ECM) deposition in mice. HKL also decreased myofibroblast activation and proliferation in UUO kidneys and NRK-49F cells. Finally, we showed that HKL treatment decreased UUO-induced mitochondrial fission and promoted mitochondrial fusion through SIRT3-dependent effects. In conclusion, activation of SIRT3 via HKL treatment might have beneficial effects on UUO-induced renal fibrosis through SIRT3-dependent regulation of mitochondrial dynamics and the NF-κB/TGF-β1/Smad signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Sirtuin 3 Activation by Honokiol Decreases Unilateral Ureteral Obstruction-Induced Renal Inflammation and Fibrosis via Regulation of Mitochondrial Dynamics and the Renal NF-κB-TGF-β1/Smad Signaling Pathway

Quan

Park

Jin

et al. 2020

IJMS

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“…Mitochondrial dysfunction causes excessive production of ROS and trigger oxidative stress and inflammatory response, which are two major factors in accelerating the progression of fibrosis (Miao et al, 2019). It is noted that mitochondrial dysfunction can lead to EMT, ECM accumulation, and renal fibrosis (Quadri, Fatima, Che, & Zhang, 2019). ER stress can activate proapoptotic pathways, induce EMT, and trigger inflammatory response, which is an important factor in the formation of organ fibrosis (Lenna & Trojanowska, 2012; Tanjore, Lawson, & Blackwell, 2013).…”

Section: Discussionmentioning

confidence: 99%

Involvement of miR‐27a‐3p in diabetic nephropathy via affecting renal fibrosis, mitochondrial dysfunction, and endoplasmic reticulum stress

Wang

Guo

et al. 2020

Journal Cellular Physiology

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Diabetic nephropathy (DN) is acknowledged as a serious chronic complication of diabetes mellitus. Nevertheless, its pathogenesis is complicated and unclear. Thus, in this study, the role of miR-27a-3p-prohibitin/TMBIM6 signaling axis in the progression of DN was elucidated. Type 2 diabetic db/db mice and high glucose (HG)-challenged HK-2 cells were used as in vivo and in vitro models. Our results showed that miR-27a-3p was upregulated and prohibitin or transmembrane BAX inhibitor motif containing 6 (TMBIM6) was downregulated in the kidney tissues of db/db mice and HG-treated HK-2 cells. Silencing miR-27a-3p enhanced the expression of prohibitin and TMBIM6 in the kidney tissues and HK-2 cells. Inhibition of miR-27a-3p improved functional injury, as evidenced by decreased blood glucose, urinary albumin, serum creatinine, and blood urea nitrogen levels. MiR-27a-3p silencing ameliorated renal fibrosis, reflected by reduced profibrogenic genes (e.g., transforming growth factor β1, fibronectin, collagen I and III, and α-smooth muscle actin). Furthermore, inhibition of miR-27a-3p relieved mitochondrial dysfunction in the kidney of db/db mice, including upregulation of mitochondrial membrane potential, complex I and III activities, adenosine triphosphate, and mitochondrial cytochrome C, as well as suppressing reactive oxygen species production. In addition, miR-27a-3p silencing attenuated endoplasmic reticulum (ER) stress, reflected by reduced expression of p-IRE1α, p-eIF2α, XBP1s, and CHOP. Mechanically, we identified prohibitin and TMBIM6 as direct targets of miR-27a-3p. Inhibition of miR-27a-3p protected HG-treated HK-2 cells from apoptosis, extracellular matrix accumulation, mitochondrial dysfunction, and ER stress by regulating prohibitin or TMBIM6. Taken together, we reveal that miR-27a-3p-prohibitin/TMBIM6 signaling axis regulates the progression of DN, which can be a potential therapeutic target.

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“…Mitochondria are power players in kidney function, and their functions are fine-tuned through the modulation of their biogenesis, bioenergetics, dynamics and clearance from cells (mitophagy) [16,17]. Mitochondrial dysfunction plays a crucial role in the pathogenesis of kidney disease and is involved in the physiological process of renal fibrosis [18]. Indeed, transcriptional analysis of biopsy samples from CKD patients showed that the pathways associated with mitochondrial function are downregulated compared to those in healthy individuals [19].…”

Section: Discussionmentioning

confidence: 99%

PGC-1α Suppresses the Activation of TGF-β/Smad Signaling via Targeting TGFβRI Downregulation by let-7b/c Upregulation

Choi¹,

Kim²,

Kim³

et al. 2019

IJMS

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TGF-β/Smad signaling is a major pathway in progressive fibrotic processes, and further studies on the molecular mechanisms of TGF-β/Smad signaling are still needed for their therapeutic targeting. Recently, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) was shown to improve renal fibrosis, making it an attractive target for chronic kidney diseases (CKDs). Here, we show the mechanism by which PGC-1α regulates the TGF-β/Smad signaling pathway using HK-2 cell lines stably overexpressing empty vector (mock cells) or human PGC1α (PGC1α cells). Stable PGC-1α overexpression negatively regulated the expression of TGF-β-induced epithelial-mesenchymal transition (EMT) markers (fibronectin, E-cadherin, vimentin, and α-SMA) and EMT-related transcription factors (Snail and Slug) compared to mock cells, inhibiting fibrotic progression. Interestingly, among molecules upstream of Smad2/3 activation, the gene expression of only TGFβRI, but not TGFβRII, was downregulated in PGC-1α cells. In addition, the downregulation of TGFβRI by PGC-1α was associated with the upregulation of let-7b/c, miRNA for which the 3′ untranslated region (UTR) of TGFβRI contains a binding site. In conclusion, PGC-1α suppresses TGF-β/Smad signaling activation via targeting TGFβRI downregulation by let-7b/c upregulation.

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Mitochondria and Renal Fibrosis

Cited by 21 publications

References 43 publications

Sirtuin 3 Activation by Honokiol Decreases Unilateral Ureteral Obstruction-Induced Renal Inflammation and Fibrosis via Regulation of Mitochondrial Dynamics and the Renal NF-κB-TGF-β1/Smad Signaling Pathway

Sirtuin 3 Activation by Honokiol Decreases Unilateral Ureteral Obstruction-Induced Renal Inflammation and Fibrosis via Regulation of Mitochondrial Dynamics and the Renal NF-κB-TGF-β1/Smad Signaling Pathway

Involvement of miR‐27a‐3p in diabetic nephropathy via affecting renal fibrosis, mitochondrial dysfunction, and endoplasmic reticulum stress

PGC-1α Suppresses the Activation of TGF-β/Smad Signaling via Targeting TGFβRI Downregulation by let-7b/c Upregulation

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