Krüppel-like factor 15 is a key suppressor of podocyte fibrosis under rotational force-driven pressure

Yu, Mi Yeon; Kim, Ji Eun; Lee, Saram; Choi, Jin Woo; Kim, Yong Chul; Han, Seung Seok; Lee, Hajeong; Hui, Ran; Lee, Jung Pyo; Lee, Jae Woo; Kim, Yon Su; Yang, Seung Hee

doi:10.1016/j.yexcr.2019.111706

Cited by 5 publications

(9 citation statements)

References 31 publications

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“…Optimal pressure conditions were evaluated for the induction of fibrosis in hPGECs. Three operating pressures were assessed, namely static, 4 mmHg, and 8 mmHg, similar to a previous study that assessed podocyte fibrosis [ 7 ]. We determined the pressure to induce fibrosis in hPGECs to be 4 mm Hg in this experiment.…”

Section: Methodsmentioning

confidence: 99%

“…We used pressurizing devices to apply pressure (4 and 8 mmHg) to the cultured hPGECs for 48 h. The change in KLF2 expression with varying pressure was confirmed and analyzed. The pressurizing device used was described in a previous study [ 7 ].…”

Section: Methodsmentioning

confidence: 99%

“…KLF6 expression in podocytes maintains mitochondrial function and prevents podocyte apoptosis [ 4 ], while KLF5 expression prevents podocyte apoptosis via the blockading of ERK/p38 MAPK pathways [ 5 ]. KLF15 is a critical regulator of podocyte differentiation and is protective against podocyte injury [ 6 , 7 , 8 ]. KLF2 mediates the functions of various types of cells, among which its role is particularly crucial in endothelial cells, and it plays a pivotal role in quiescence, shear stress regulation, homeostasis, and vasculogenesis [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…In vitro studies on hypertension have been conducted using different methods, including increasing atmospheric pressure in an incubator [ 51 ] and using a “glomerulus-on-a-chip” microfluidic device [ 52 ]. In a previous study, we developed a novel device that applied rotational force to cultured cells and created a hypertensive condition using this method [ 7 ]. Using this machine, pressure was applied on glomerular endothelial cells by simulating a hypertensive environment similar to increased BP of the human body, and the cell damage caused by the exerted pressure was evaluated.…”

Section: Introductionmentioning

confidence: 99%

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Renoprotective Effect of KLF2 on Glomerular Endothelial Dysfunction in Hypertensive Nephropathy

Bae

Moon

et al. 2022

Cells

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Kruppel-like factor 2 (KLF2) regulates endothelial cell metabolism; endothelial dysfunction is associated with hypertension and is a predictor of atherosclerosis development and cardiovascular events. Here, we investigated the role of KLF2 in hypertensive nephropathy by regulating KLF2 expression in human primary glomerular endothelial cells (hPGECs) and evaluating this expression in the kidney tissues of a 5/6 nephrectomy mouse model as well as patients with hypertension. Hypertension-mimicking devices and KLF2 siRNA were used to downregulate KLF2 expression, while the expression of KLF2 was upregulated by administering simvastatin. After 4 mmHg of pressure was applied on hPGECs for 48 h, KLF2 mRNA expression decreased, while alpha-smooth muscle actin (αSMA) mRNA expression increased. Apoptosis and fibrosis rates were increased under pressure, and these phenomena were aggravated following KLF2 knockdown, but were alleviated after simvastatin treatment; additionally, these changes were observed in angiotensin II, angiotensin type-1 receptor (AT1R) mRNA, and interleukin-18 (IL-18), but not in angiotensin type-2 receptor mRNA. Reduced expression of KLF2 in glomerular endothelial cells due to hypertension was found in both 5/6 nephrectomy mice and patients with hypertensive nephropathy. Thus, our study demonstrates that the pressure-induced apoptosis and fibrosis of glomerular endothelial cells result from angiotensin II, AT1R activation, and KLF2 inhibition, and are associated with IL-18.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Renoprotective Effect of KLF2 on Glomerular Endothelial Dysfunction in Hypertensive Nephropathy

Bae

Moon

et al. 2022

Cells

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“…Notably, fluidic shear stress due to flow enhanced podocyte maturation as evidenced by higher levels of nephrin and synaptopodin expression as well as increased formation of foot process-like structures compared with static culture (Homan et al, 2019). In contrast, the application of light pressures of 4-8 mmHg reduced expression of WT1 and the differentiation marker KLF15 in primary human podocytes while increasing expression of fibronectin, an indicator of podocyte fibrosis (Yu et al, 2020).…”

Section: Glomerulus Modelsmentioning

confidence: 96%

Organotypic and Microphysiological Human Tissue Models for Drug Discovery and Development—Current State-of-the-Art and Future Perspectives

et al. 2022

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Intestinal microbiota by angiotensin receptor blocker therapy exerts protective effects against hypertensive damages

Li,

Wang,

Yan

et al. 2024

iMeta

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Dysbiosis of the gut microbiota has been implicated in hypertension, and drug–host–microbiome interactions have drawn considerable attention. However, the influence of angiotensin receptor blocker (ARB)‐shaped gut microbiota on the host is not fully understood. In this work, we assessed the alterations of blood pressure (BP), vasculatures, and intestines following ARB‐modified gut microbiome treatment and evaluated the changes in the intestinal transcriptome and serum metabolome in hypertensive rats. Hypertensive patients with well‐controlled BP under ARB therapy were recruited as human donors, spontaneously hypertensive rats (SHRs) receiving normal saline or valsartan were considered animal donors, and SHRs were regarded as recipients. Histological and immunofluorescence staining was used to assess the aorta and small intestine, and 16S rRNA amplicon sequencing was performed to examine gut bacteria. Transcriptome and metabonomic analyses were conducted to determine the intestinal transcriptome and serum metabolome, respectively. Notably, ARB‐modified fecal microbiota transplantation (FMT), results in marked decreases in systolic BP levels, collagen deposition and reactive oxygen species accumulation in the vasculature, and alleviated intestinal structure impairments in SHRs. These changes were linked with the reconstruction of the gut microbiota in SHR recipients post‐FMT, especially with a decreased abundance of Lactobacillus, Aggregatibacter, and Desulfovibrio. Moreover, ARB‐treated microbes contributed to increased intestinal Ciart, Per1, Per2, Per3, and Cipc gene levels and decreased Nfil3 and Arntl expression were detected in response to ARB‐treated microbes. More importantly, circulating metabolites were dramatically reduced in ARB‐FMT rats, including 6beta‐Hydroxytestosterone and Thromboxane B2. In conclusion, ARB‐modified gut microbiota exerts protective roles in vascular remodeling and injury, metabolic abnormality and intestinal dysfunctions, suggesting a pivotal role in mitigating hypertension and providing insights into the cross‐talk between antihypertensive medicines and the gut microbiome.

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Krüppel-like factor 15 is a key suppressor of podocyte fibrosis under rotational force-driven pressure

Cited by 5 publications

References 31 publications

Renoprotective Effect of KLF2 on Glomerular Endothelial Dysfunction in Hypertensive Nephropathy

Renoprotective Effect of KLF2 on Glomerular Endothelial Dysfunction in Hypertensive Nephropathy

Organotypic and Microphysiological Human Tissue Models for Drug Discovery and Development—Current State-of-the-Art and Future Perspectives

Intestinal microbiota by angiotensin receptor blocker therapy exerts protective effects against hypertensive damages

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