PACS-2 attenuates diabetic kidney disease via the enhancement of mitochondria-associated endoplasmic reticulum membrane formation

AbstractThe altered homeostasis of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) was closely associated with the pathological process of nervous system diseases and insulin resistance. Here, the exact implication of phosphofurin acidic cluster sorting protein 2 (PCAS-2), an anchor protein in the MAM interface, in diabetic kidney disease was investigated. In the kidneys of type 1 and type 2 diabetes mice and HG-induced HK-2 cells, a notable disruption of ER-mitochondria interactions, accompanied by a decreased PACS-2 expression in all subcellular fractions. Furthermore, PACS-2 knockout mice with diabetes displayed accelerated development of proteinuria, deterioration of kidney function, and aggravated disruption of MAM area, ER stress, mitochondrial dysfunction, renal apoptosis, and fibrosis. However, overexpression of PACS-2 effectively protected diabetic kidneys and HG-treated HK-2 cells from renal tubular impairments. Importantly, experimental uncoupling of ER-mitochondria contacts reversed the protective effects of PACS-2 restoration on HK-2 cells under HG conditions. In summary, our data indicate a pivotal role of PACS-2 in the development of diabetic renal tubular injury via the stabilization of MAM.

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Ginkgo Biloba Extract EGB761 Ameliorates the Extracellular Matrix Accumulation and Mesenchymal Transformation of Renal Tubules in Diabetic Kidney Disease by Inhibiting Endoplasmic Reticulum Stress

BioMed Research International ◽

10.1155/2021/6657206 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Jiarui Han ◽

Xinxin Pang ◽

Xiujie Shi ◽

Yage Zhang ◽

Zining Peng ◽

...

Keyword(s):

Extracellular Matrix ◽

Endoplasmic Reticulum ◽

Kidney Disease ◽

Endoplasmic Reticulum Stress ◽

Ginkgo Biloba ◽

Diabetic Kidney Disease ◽

Ginkgo Biloba Extract ◽

Collagen Iv ◽

Diabetic Kidney ◽

Renal Tubular

The study is aimed at investigating the effects of Ginkgo biloba extract EGB761 on renal tubular damage and endoplasmic reticulum stress (ERS) in diabetic kidney disease (DKD). A total of 50 C57BL/6 N mice were randomly divided into the normal group, DKD group, DKD+EGB761 group (36 mg/kg), and DKD+4-phenylbutyrate (4-PBA) group (1 g/kg). The DKD model was replicated by high-fat diet combined with intraperitoneal injection of streptozotocin (STZ). Renal tubular epithelial cells (HK-2) were divided into the control group, high-glucose group (30 mmol/L), EGB761 group (40 mg/L, 20 mg/L, 10 mg/L), TM group, and TM+4-PBA group. After 8 weeks of administration, expressions of serum creatinine (Scr), blood urea nitrogen (BUN), 24 h urinary protein (24 h Pro), fasting blood glucose (FBG), β2-microglobulin (β2-MG), and retinol binding protein 4 (RBP4) of mice were tested. The pathological changes of renal tissue were observed. The expressions of extracellular matrix (ECM) accumulation and epithelial-mesenchymal transition (EMT) markers α-smooth muscle actin (α-SMA), E-cadherin, fibronectin, and collagen IV, as well as the ERS markers GRP78 and ATF6, were tested by Western blot, qPCR, immunohistochemistry, or immunofluorescence. EGB761 could decrease the Scr, BUN, 24 h Pro, and FBG levels in the DKD group, alleviate renal pathological injury, decrease urine β2-MG, RBP4 levels, and decrease the expression of α-SMA, collagen IV, fibronectin, and GRP78, as well as ATF6, while increase the expression of E-cadherin. These findings demonstrate that EGB761 can improve renal function, reduce tubular injury, and ameliorate ECM accumulation and EMT in DKD kidney tubules, and the mechanism may be related to the inhibition of ERS.

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Role of p53/miR-155-5p/sirt1 loop in renal tubular injury of diabetic kidney disease

Journal of Translational Medicine ◽

10.1186/s12967-018-1486-7 ◽

2018 ◽

Vol 16 (1) ◽

Cited By ~ 27

Author(s):

Yue Wang ◽

Zong-ji Zheng ◽

Yi-jie Jia ◽

Yan-lin Yang ◽

Yao-ming Xue

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Tubular Injury ◽

Diabetic Kidney ◽

Renal Tubular

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The role of CDX2 in renal tubular lesions during diabetic kidney disease

Aging ◽

10.18632/aging.202537 ◽

2021 ◽

Vol 13 (5) ◽

pp. 6782-6803

Author(s):

Huiming Liu ◽

Rui Yan ◽

Luqun Liang ◽

Huifang Zhang ◽

Jiayi Xiang ◽

...

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Diabetic Kidney ◽

Renal Tubular

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Role of Nox2 in diabetic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00511.2012 ◽

2013 ◽

Vol 304 (7) ◽

pp. F840-F848 ◽

Cited By ~ 65

Author(s):

Young-Hyun You ◽

Shinichi Okada ◽

San Ly ◽

Karin Jandeleit-Dahm ◽

David Barit ◽

...

Keyword(s):

Blood Pressure ◽

Type 1 Diabetes ◽

Kidney Disease ◽

Systolic Blood Pressure ◽

Diabetic Kidney Disease ◽

Microvascular Complications ◽

Macrophage Infiltration ◽

Diabetic Kidney

NADPH oxidase (Nox) isoforms have been implicated in contributing to diabetic microvascular complications, but the functional role of individual isoforms in diabetic kidney are unclear. Nox2, in particular, is highly expressed in phagocytes and may play a key inflammatory role in diabetic kidney disease. To determine the role of Nox2, we evaluated kidney function and pathology in wild-type (WT; C57BL/6) and Nox2 knockout (KO) mice with type 1 diabetes. Diabetes was induced in male Nox2 KO and WT mice with a multiple low-dose streptozotocin protocol. Groups were studied for kidney disease after 8 and 20 wk of diabetes. Hyperglycemia and body weights were similar in WT and Nox2 KO diabetic mice. All functional and structural features of early and later stage diabetic kidney disease (albuminuria, mesangial matrix, tubulointerstitial disease, and gene expression of matrix and transforming growth factor-β) were similar in both diabetic groups compared with their respective nondiabetic groups, except for reduction of macrophage infiltration and monocyte chemoattractant protein-1 in the diabetic Nox2 KO mice. Systolic blood pressure by telemetry was surprisingly increased in Nox2 KO mice; however, the systolic blood pressure was reduced in the diabetic WT and Nox2 KO mice by tail-cuff. Interestingly, diabetic Nox2 KO mice had marked upregulation of renal Nox4 at both the glomerular and cortical levels. The present results demonstrate that lack of Nox2 does not protect against diabetic kidney disease in type 1 diabetes, despite a reduction in macrophage infiltration. The lack of renoprotection may be due to upregulation of renal Nox4.

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