PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease

Zhao, Chanyue; Li, Li; Li, Chenrui; Tang, Chengyuan; Cai, Juan; Liu, Yu; Yang, Jinfei; Xi, Yiyun; Yang, Ming; Jiang, Na; Han, Yachun; Liu, Yan; Luo, Shilu; Xiao, Li; Sun, Lin

doi:10.1186/s10020-022-00545-x

Cited by 12 publications

(9 citation statements)

References 49 publications

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“…HFD and STZ combination is a well‐known approach for studying diabetic nephropathy 25,26 . A total of 30 four‐week‐old male C57BL/6 mice were purchased from Hunan SJA Laboratory Animal Co. Ltd. (Hunan, China).…”

Section: Methodsmentioning

confidence: 99%

PCSK9 causes inflammation and cGAS/STING pathway activation in diabetic nephropathy

Feng,

Liao,

Peng

et al. 2023

The FASEB Journal

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Our previous research revealed that an increase in PCSK9 is linked to aggravated inflammation in the kidneys of mice affected by a high‐fat diet and streptozotocin (HFD/STZ) or in HGPA‐induced HK‐2 cells. Furthermore, the cGAS/STING pathway has been reported to be involved in diabetic nephropathy (DN). Therefore, in this study, we aimed to examine the correlation between the proinflammatory effect of PCSK9 and the cGAS/STING pathway in DN. We used PCSK9 mAbs to inhibit PCSK9 in vivo and PCSK9 siRNA in vitro and measured the inflammatory phenotype in HFD/STZ‐treated mice or HGPA‐induced HK‐2 cells, and observed decreased blood urea nitrogen, creatinine, UACR, and kidney injury in response to the PCSK9 mAb in HFD/STZ‐treated mice. Moreover, IL‐1 β, MCP‐1, and TNF‐α levels were reduced by the PCSK9 mAb in vivo and PCSK9 siRNA in vitro. We observed increased mtDNA damage and activation of the cGAS‐STING signaling pathway during DN, as well as the downstream targets p‐TBK1, p‐NF‐κB p65, and IL‐1β. In a further experiment with an HGPA‐induced DN model in HK‐2 cells, we revealed that mtDNA damage was increased, which led to the activation of the cGAS/STING system and its downstream targets. Notably, the cGAS‐STING signaling pathway was inhibited by the PCSK9 mAb in vivo and PCSK9 siRNA in vitro. In addition, inhibition of STING with C‐176 in HGPA‐induced HK‐2 cells markedly blocked inflammation. In conclusion, we report for the first time that PCSK9 triggers mitochondrial DNA damage and activates the cGAS‐STING pathway in DN, which leads to a series of inflammation cascades. PCSK9‐targeted intervention can effectively reduce DN inflammation and delay its progression. Moreover, the inhibition of STING significantly abrogated the inflammation triggered by HGPA in HK‐2 cells.

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Section: Methodsmentioning

confidence: 99%

PCSK9 causes inflammation and cGAS/STING pathway activation in diabetic nephropathy

Feng,

Liao,

Peng

et al. 2023

The FASEB Journal

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“…In studies involving streptozotocin-induced diabetic mice and DKD patients, reduced levels of PACS-2 expression have been observed. Notably, diabetic tubule-specific Pacs-2 deletion accentuates lipid synthesis through upregulated sterol O-acyltransferase 1 (SOAT1) expression and concurrent inhibition of cholesterol efflux ( 87 ). This intensified lipid accumulation in tubular cells contributes to the progression of albuminuria excretion and exacerbates kidney damage.…”

Section: Mechanisms Of Renal Tubular Injuries In Dkdmentioning

confidence: 99%

Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms

Xu,

Ha,

Yang

et al. 2023

Front. Endocrinol.

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Diabetic kidney disease (DKD) is a serious complication of diabetes that can lead to end-stage kidney disease. Despite its significant impact, most research has concentrated on the glomerulus, with little attention paid to the tubulointerstitial region, which accounts for the majority of the kidney volume. DKD’s tubulointerstitial lesions are characterized by inflammation, fibrosis, and loss of kidney function, and recent studies indicate that these lesions may occur earlier than glomerular lesions. Evidence has shown that inflammatory mechanisms in the tubulointerstitium play a critical role in the development and progression of these lesions. Apart from the renin-angiotensin-aldosterone blockade, Sodium-Glucose Linked Transporter-2(SGLT-2) inhibitors and new types of mineralocorticoid receptor antagonists have emerged as effective ways to treat DKD. Moreover, researchers have proposed potential targeted therapies, such as inhibiting pro-inflammatory cytokines and modulating T cells and macrophages, among others. These therapies have demonstrated promising results in preclinical studies and clinical trials, suggesting their potential to treat DKD-induced tubulointerstitial lesions effectively. Understanding the immune-inflammatory mechanisms underlying DKD-induced tubulointerstitial lesions and developing targeted therapies could significantly improve the treatment and management of DKD. This review summarizes the latest advances in this field, highlighting the importance of focusing on tubulointerstitial inflammation mechanisms to improve DKD outcomes.

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“…The study by Chen et al found that inhibition of DsbA-L expression aggravated lipid deposition in DKD, and activation of the AMPK pathway is a potential mechanism by which DsbA-L plays a role in renal lipid deposition 110 . Zhao et al found that diabetic mice with proximal tubule PACS2-specific knockout had more severe tubular damage and proteinuria than controls, which was accompanied by increased lipid synthesis, decreased cholesterol uptake and efflux, and lipid deposition in renal tubules 111 , indicating that PACS2 is a major regulator in lipid-related kidney lesions in DKD. These studies suggested that MAM-related proteins played key roles in regulating lipid deposition in DKD, but more research is needed to elucidate the molecular mechanism of MAM involvement in EFD in DKD.…”

Section: The Role Of Mam In Dkdmentioning

confidence: 99%

Broadening horizons: the contribution of mitochondria-associated endoplasmic reticulum membrane (MAM) dysfunction in diabetic kidney disease

Liu,

Qiao,

Pan

et al. 2023

Int. J. Biol. Sci.

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Diabetic kidney disease (DKD) is a global health issue that presents a complex pathogenesis and limited treatment options. To provide guidance for precise therapies, it is crucial to accurately identify the pathogenesis of DKD. Several studies have recognized that mitochondrial and endoplasmic reticulum (ER) dysfunction are key drivers of the pathogenesis of DKD. The mitochondria-associated ER membrane (MAM) is a dynamic membrane contact site (MSC) that connects the ER and mitochondria and is essential in maintaining the normal function of the two organelles. MAM is involved in various cellular processes, including lipid synthesis and transport, calcium homeostasis, mitochondrial fusion and fission, and ER stress. Meanwhile, recent studies confirm that MAM plays a significant role in the pathogenesis of DKD by regulating glucose metabolism, lipid metabolism, inflammation, ER stress, mitochondrial fission and fusion, and autophagy. Herein, this review aims to provide a comprehensive summary of the physiological function of MAMs and their impact on the progression of DKD. Subsequently, we discuss the trend of pharmaceutical studies that target MAM resident proteins for treating DKD. Furthermore, we also explore the future development prospects of MAM in DKD research, thereby providing a new perspective for basic studies and clinical treatment of DKD.

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PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease

Cited by 12 publications

References 49 publications

PCSK9 causes inflammation and cGAS/STING pathway activation in diabetic nephropathy

PCSK9 causes inflammation and cGAS/STING pathway activation in diabetic nephropathy

Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms

Broadening horizons: the contribution of mitochondria-associated endoplasmic reticulum membrane (MAM) dysfunction in diabetic kidney disease

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