Profile of Podocyte Translatome During Development of Type 2 and Type 1 Diabetic Nephropathy Using Podocyte-Specific TRAP mRNA RNA-seq

Wang, Yinqiu; Niu, Aolei; Pan, Yu; Cao, Shirong; Terker, Andrew S.; Wang, Suwan; Fan, Xiaofeng; Toth, Cynthia L.; Solano, Marisol A. Ramirez; Michell, Danielle L.; Contreras, Danielle; Allen, Ryan M.; Zhu, Wanying; Sheng, Quanhu; Fogo, Agnes B.; Vickers, Kasey C.; Zhang, Mingzhi; Harris, Raymond C.

doi:10.2337/db21-0110

Cited by 14 publications

(17 citation statements)

References 58 publications

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“…To identify the candidate genes involved in podocyte damage in DKD progression, we used the single-nucleus RNA sequencing (snRNA-seq) database from kidney of DKD patients to screen differentially expressed genes. Consistent with the results reported in previous studies, [15][16][17][18] the downregulated molecule membrane-associated guanylate kinase inverted 2 (MAGI2) was specific expression in podocytes and correlated with podocyte loss in DKD. MAGI2, a member of the MAGUK family of scaffolding proteins, contains 5 PDZ domains, 2 WW domains, an SH3 domain, and a catalytically inactive guanylate kinase domain.…”

Section: Introductionsupporting

confidence: 90%

MAGI2 ameliorates podocyte apoptosis of diabetic kidney disease through communication with TGF‐β‐Smad3/nephrin pathway

Wang,

Li,

Wang

et al. 2023

The FASEB Journal

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Podocytes, the key component of the glomerular filtration barrier (GFB), are gradually lost during the progression of diabetic kidney disease (DKD), severely compromising kidney functionality. The molecular mechanisms regulating the survival of podocytes in DKD are incompletely understood. Here, we show that membrane‐associated guanylate kinase inverted 2 (MAGI2) is specifically expressed in renal podocytes, and promotes podocyte survival in DKD. We found that MAGI2 expression was downregulated in podocytes cultured with high‐glucose in vitro, and in kidneys of db/db mice as well as DKD patients. Conversely, we found enforced expression of MAGI2 via AAV transduction protected podocytes from apoptosis, with concomitant improvement of renal functions. Mechanistically, we found that MAGI2 deficiency induced by high glucose levels activates TGF‐β signaling to decrease the expression of anti‐apoptotic proteins. These results indicate that MAGI2 protects podocytes from cell death, and can be harnessed therapeutically to improve renal function in diabetic kidney disease.

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Section: Introductionsupporting

confidence: 90%

MAGI2 ameliorates podocyte apoptosis of diabetic kidney disease through communication with TGF‐β‐Smad3/nephrin pathway

Wang,

Li,

Wang

et al. 2023

The FASEB Journal

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“…This mouse line has features similar to that from the Jackson Laboratory ( ): Significant increases in the body weight starting at 4 wk, hyperglycemia (6-h fasting blood glucose and hemoglobin A1c) at 8 wk, insulinemia (> 3-fold) at 8 wk, and hyperlipidemia (cholesterol, triglyceride, and low-density lipoprotein) along with the early onset of renal dysfunction (indicated by significantly increased microalbumin level in 24-h urine analysis) at 12 wk of age. Therefore, this mouse line has been widely used as a model for studies on type 2 diabetes[ 19 , 20 ], including for the studies on DN of type 2 diabetes[ 18 , 21 ].…”

Section: Methodsmentioning

confidence: 99%

“…We have previously shown that clopidogrel significantly reduced renal collagen and fibronectin (FN) expression and thus ameliorated diabetes-induced renal fibrosis in a streptozotocin-induced murine model of type 1 diabetes[ 17 ]. However, because 80%-90% of the population with diabetes has type 2 disease[ 1 ], in the present study, we aimed to determine whether clopidogrel treatment has a preventive or therapeutic effect in the kidneys of obese type 2 diabetic db / db mice, a widely used mouse model of type 2 diabetes for DN investigations[ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Clopidogrel delays and can reverse diabetic nephropathy pathogenesis in type 2 diabetic db/db mice

Li¹,

Liu²,

Zheng³

et al. 2022

WJD

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BACKGROUND Diabetic nephropathy (DN) is the principal cause of end-stage renal disease. Previous studies have shown that clopidogrel can prevent the early progression of renal injury. AIM To elucidate whether clopidogrel is beneficial against DN by using a db / db mouse model. METHODS db/db mice with a higher urinary albumin/creatinine ratio (ACR) relative to age- and sex-matched wild-type control mice were randomly allocated to clopidogrel and vehicle treatment groups. Clopidogrel was administered at doses of 5, 10, and 20 mg/kg by gavage for 12 wk. Body mass, blood glucose level, and urinary creatinine and albumin concentrations in each group were measured before and after the intervention. Renal fibrosis was evaluated using periodic acid-Schiff and Masson’s trichrome staining. The renal protein expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and F4/80 was assessed using immunohistochemistry. Urinary TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-6 levels were analyzed using enzyme-linked immunosorbent assay; TNF-α and IL-1β mRNA expression was measured using real-time quantitative polymerase chain reaction. The protein expression of fibronectin (FN) and collagen I was assessed using immunohistochemistry. RESULTS Clopidogrel treatment did not affect the body mass or blood glucose level of the db/db mice; however, it increased bleeding time and reduced urinary ACR in a dose-dependent manner. Immunohistochemical staining revealed an amelioration of renal fibrosis, significantly lower deposition of FN and collagen I, and significantly lower expression of the proinflammatory cytokines TNF-α and IL-1β and lower levels of urinary TNF-α and MCP-1 in the clopidogrel-treated db/db mice ( P < 0.05). Furthermore, clopidogrel significantly reduced macrophage infiltration into the glomeruli of the db/db mice. CONCLUSION Clopidogrel significantly reduced renal collagen deposition and fibrosis and prevented renal dysfunction in db / db mice, most likely through inhibition of renal macrophage infiltration and the associated inflammation.

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“…The decreased number of podocytes is associated with proteinuria and glomerular structural damage in diabetic nephropathy [ 105 , 106 ]. Podocyte apoptosis and the subsequent podocyte depletion may indeed represent early events affecting the diabetic kidney and underlying diabetic glomerulopathy, which leads to diabetic nephropathy in type I and type II diabetes [ 107 , 108 ]. Podocyte apoptosis coincides with the onset of diabetes and hyperglycemia in type I and type II diabetes, indicating that glucotoxicity may be underlying the stimulation of pro-apoptotic signaling and subsequent podocyte injury in diabetic kidneys.…”

Section: Apoptosis In Diabetic Nephropathymentioning

confidence: 99%

Programmed Cell Death in Diabetic Nephropathy: A Review of Apoptosis, Autophagy, and Necroptosis

Erekat

2022

Med Sci Monit

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Diabetic nephropathy is a common complication of type I and type II diabetes, in which renal glomeruli are destroyed, resulting in renal damage, proteinuria, and hypertension. Apoptosis, autophagy, and necroptosis are 3 forms of programmed cell death that have been implicated in the pathogenesis of diabetic nephropathy. Apoptosis of podocytes leads to glomerular injury and podocyte depletion, which are associated with proteinuria and glomerular structural damage in diabetic nephropathy. Additionally, epithelial cells in the proximal convoluted tubules also undergo apoptosis in diabetic nephropathy, leading to tubular atrophy, which causes tubular cell depletion and the subsequent formation of atubular glomeruli in association with the loss of renal function. On the other hand, insufficiency of autophagy has been correlated with the pathogenesis of diabetic nephropathy. For instance, decreased autophagic activity has been shown in podocytes of the diabetic kidney, causing variations in podocyte function and subsequent disruption to the glomerular filtration barrier. Furthermore, attenuated autophagic activity has also been demonstrated in proximal tubular cells of the diabetic kidney, resulting in the buildup of impaired molecules and organelles, which are normally broken down by autophagy, leading to proteinuria. Moreover, necroptosis might have a key role in podocyte damage and subsequent decline in diabetic nephropathy. Thus, this article aims to review the mechanisms and effects of programmed cell death in diabetic nephropathy, including the roles of apoptosis, autophagy, and necroptosis.

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Profile of Podocyte Translatome During Development of Type 2 and Type 1 Diabetic Nephropathy Using Podocyte-Specific TRAP mRNA RNA-seq

Cited by 14 publications

References 58 publications

MAGI2 ameliorates podocyte apoptosis of diabetic kidney disease through communication with TGF‐β‐Smad3/nephrin pathway

MAGI2 ameliorates podocyte apoptosis of diabetic kidney disease through communication with TGF‐β‐Smad3/nephrin pathway

Clopidogrel delays and can reverse diabetic nephropathy pathogenesis in type 2 diabetic db/db mice

Programmed Cell Death in Diabetic Nephropathy: A Review of Apoptosis, Autophagy, and Necroptosis

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