Regulation of Nephrin Phosphorylation in Diabetes and Chronic Kidney Injury

Denhez, Benoît; Geraldes, Pedro

doi:10.1007/5584_2017_62

Cited by 15 publications

(15 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Foot process fusion caused by podocyte injury is the main mechanism of glomerular proteinuria. 16,17 Clinical studies have shown that podocyte injury appeared in the early stage of the disease, and was accompanied by podocyte retraction, widening, fusion, and disappearance. Additionally, kidney biopsies of DN patients and animal models showed foot process disappearance and a decrease in podocytes by concomitant degrees of proteinuria.…”

Section: Discussionmentioning

confidence: 99%

<p>The Effects of Puerarin on Autophagy Through Regulating of the PERK/eIF2α/ATF4 Signaling Pathway Influences Renal Function in Diabetic Nephropathy</p>

Xu¹,

Chen²,

QiChun³

et al. 2020

DMSO

View full text Add to dashboard Cite

Background and Purpose: Autophagy is the main protective mechanism against aging in podocytes, which are terminally differentiated cells that have a very limited capacity for mitosis and self-renewal. Here, a streptozotocin-induced DN C57BL/6 mouse model was used to investigate the effects of puerarin on the modulation of autophagy under conditions associated with endoplasmic reticulum stress (ERS). In addition, this study aimed to identify the potential underlying molecular mechanisms. Methods and Results: DN C57BL/6 mouse model was induced by streptozotocin (150 mg/ kg) injection. The mice were administered rapamycin and puerarin, respectively, daily for up to 8 weeks. After the serum and kidney samples were collected, the fasting blood glucose (FBG), parameters of renal function, histomorphology, and the podocyte functional proteins were analyzed. Moreover, the autophagy markers and the expressions of PERK/ATF4 pathway were studied in kidney. Results found that the FBG level in DN mice was significantly higher than in normal mice. Compared with DN model mice, puerarin-treated mice showed an increased expression of podocyte functional proteins, including nephrin, podocin, and podocalyxin. Furthermore, the pathology and structure alterations were improved by treatment with rapamycin and puerarin compared with the DN control. The results indicated an elevated level of autophagy in rapamycin and puerarin groups compared with the DN model, as demonstrated by the upregulated expression of autophagy markers Beclin-1, LC3II, and Atg5, and downregulated p62 expression. In addition, the levels of PERK, eIF2α, and ATF4 were reduced in the DN model, which was partially, but significantly, prevented by rapamycin and puerarin. Conclusion: This study emphasizes the renal-protective effects of puerarin in DN mice, particularly in the modulation of autophagy under ERS conditions, which may be associated with activation of the PERK/eIF2α/ATF4 signaling pathway. Therefore, PERK may be a potential target for DN treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

<p>The Effects of Puerarin on Autophagy Through Regulating of the PERK/eIF2α/ATF4 Signaling Pathway Influences Renal Function in Diabetic Nephropathy</p>

Xu¹,

Chen²,

QiChun³

et al. 2020

DMSO

View full text Add to dashboard Cite

show abstract

“…Interestingly, C1-Ten is upregulated in diabetic nephropathy (DN) models and is associated with induction of podocyte hypertrophy ( 99 ). Increased levels of SHP-1 phosphatase have likewise been identified in models of DN ( 74 , 94 – 98 ) resulting in reduced phosphorylation of Y1176, Y1193, and Y1217, and disruption of nephrin and Nck binding. These recent findings position global reductions in nephrin tyrosine phosphorylation as a mechanism of damage in DN, the most common form of CKD.…”

Section: Phosphatase-mediated Regulation Of Nephrin Tyrosine Phosphormentioning

confidence: 94%

“…PTP-1B, which is upregulated in the puromycin aminonucleoside (PAN) model of membranous nephropathy (MN), can directly dephosphorylate rat tyrosine residues that correlate to the human sites 1193 and 1217 ( 67 ). Likewise, the SHP-1 phosphatase, which binds group A tyrosine residues, dephosphorylates tyrosines 1176, 1193, and 1217 ( 74 ) and its upregulation has been observed in instances of hyperglycemia and diabetes by several groups ( 74 , 94 – 98 ). In podocytes, hyperglycemia induces a persistent increase in SHP-1 expression, due to epigenetic modification in the SHP-1 promoter ( 97 ), leading to insulin signaling resistance, podocyte dysfunction, and cell death.…”

Section: Phosphatase-mediated Regulation Of Nephrin Tyrosine Phosphormentioning

confidence: 99%

“…The role of nephrin signaling during disease has remained an intense area of interest since the discovery of reduced phosphorylation of group B tyrosine residues in instances of human disease and in various disease models. Alterations in phosphorylation of group B tyrosines has been described in minimal change disease (MCD) ( 100 ) and MN ( 101 ) as well as in the PAN ( 76 , 82 ), protamine sulfate ( 54 , 102 ), nephrotoxic serum (NTS) ( 75 , 88 , 103 ), and lipopolysaccharide ( 102 ) rodent injury models and type I diabetic Akita mice ( 74 , 98 ). Similarly, altered levels of several phosphatases known to influence nephrin’s phospho-status have also been identified in instances of disease ( 104 ).…”

Section: Disruption Of Nephrin Tyrosine Phosphorylation In Podocyte-bmentioning

confidence: 99%

See 1 more Smart Citation

Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond

2018

View full text Add to dashboard Cite

Podocytes are a major component of the glomerular blood filtration barrier, and alterations to the morphology of their unique actin-based foot processes (FP) are a common feature of kidney disease. Adjacent FP are connected by a specialized intercellular junction known as the slit diaphragm (SD), which serves as the ultimate barrier to regulate passage of macromolecules from the blood. While the link between SD dysfunction and reduced filtration selectivity has been recognized for nearly 50 years, our understanding of the underlying molecular circuitry began only 20 years ago, sparked by the identification of NPHS1, encoding the transmembrane protein nephrin. Nephrin not only functions as the core component of the extracellular SD filtration network but also as a signaling scaffold via interactions at its short intracellular region. Phospho-regulation of several conserved tyrosine residues in this region influences signal transduction pathways which control podocyte cell adhesion, shape, and survival, and emerging studies highlight roles for nephrin phospho-dynamics in mechanotransduction and endocytosis. The following review aims to summarize the last 5 years of advancement in our knowledge of how signaling centered at nephrin directs SD barrier formation and function. We further provide insight on promising frontiers in podocyte biology, which have implications for SD signaling in the healthy and diseased kidney.

show abstract

“…Severe injury of the slit diaphragm complex lead to loss or effacement of podocyte foot process and, which contributes to protein uric renal injury [4,5]. In addition, the disruption of the filtration barrier observed in diabetic nephrotic diseases, is due to damage of proteins within the slit diaphragm such as nephrin [6]. Accordingly, the podocytes can be a potential therapeutic target in diabetic nephropathy (DN).…”

Section: Introductionmentioning

confidence: 99%

Tangeretin Ameliorates Glucose-Induced Podocyte Injury through Blocking Epithelial to Mesenchymal Transition Caused by Oxidative Stress and Hypoxia

Kang

Kim

et al. 2020

IJMS

View full text Add to dashboard Cite

Podocyte injury inevitably results in leakage of proteins from the glomerular filter and is vital in the pathogenesis of diabetic nephropathy (DN). The underlying mechanisms of podocyte injury facilitate finding of new therapeutic targets for DN treatment and prevention. Tangeretin is an O-polymethoxylated flavone present in citrus peels with anti-inflammatory and antioxidant properties. This study investigated the renoprotective effects of tangeretin on epithelial-to-mesenchymal transition-mediated podocyte injury and fibrosis through oxidative stress and hypoxia caused by hyperglycemia. Mouse podocytes were incubated in media containing 33 mM glucose in the absence and presence of 1–20 μM tangeretin for up to 6 days. The in vivo animal model employed db/db mice orally administrated with 10 mg/kg tangeretin for 8 weeks. Non-toxic tangeretin inhibited glucose-induced expression of the mesenchymal markers of N-cadherin and α-smooth muscle actin in podocytes. However, the reduced induction of the epithelial markers of E-cadherin and P-cadherin was restored by tangeretin in diabetic podocytes. Further, tangeretin enhanced the expression of the podocyte slit diaphragm proteins of nephrin and podocin down-regulated by glucose stimulation. The transmission electron microscopic images revealed that foot process effacement and loss of podocytes occurred in diabetic mouse glomeruli. However, oral administration of 10 mg/kg tangeretin reduced urine albumin excretion and improved foot process effacement of diabetic podocytes through inhibiting loss of slit junction and adherenes junction proteins. Glucose enhanced ROS production and HIF-1α induction in podocytes, leading to induction of oxidative stress and hypoxia. Similarly, in diabetic glomeruli reactive oxygen species (ROS) production and HIF-1α induction were observed. Furthermore, hypoxia-evoking cobalt chloride induced epithelial-to-mesenchymal transition (EMT) process and loss of slit diaphragm proteins and junction proteins in podocytes, which was inhibited by treating submicromolar tangeretin. Collectively, these results demonstrate that tangeretin inhibited podocyte injury and fibrosis through blocking podocyte EMT caused by glucose-induced oxidative stress and hypoxia.

show abstract

Regulation of Nephrin Phosphorylation in Diabetes and Chronic Kidney Injury

Cited by 15 publications

References 81 publications

<p>The Effects of Puerarin on Autophagy Through Regulating of the PERK/eIF2α/ATF4 Signaling Pathway Influences Renal Function in Diabetic Nephropathy</p>

<p>The Effects of Puerarin on Autophagy Through Regulating of the PERK/eIF2α/ATF4 Signaling Pathway Influences Renal Function in Diabetic Nephropathy</p>

Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond

Tangeretin Ameliorates Glucose-Induced Podocyte Injury through Blocking Epithelial to Mesenchymal Transition Caused by Oxidative Stress and Hypoxia

Contact Info

Product

Resources

About