Role of protein phosphatase 2A in kidney disease (Review)

Shao, Lishi; Ma, Yiqun; Fang, Qixiang; Huang, Zhuowei; Wan, Shanshan; Wang, Jiaping; Li, Yang

doi:10.3892/etm.2021.10671

Cited by 9 publications

(11 citation statements)

References 126 publications

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“…Various studies demonstrated that the physiological role of POP is to regulate PP2A; particularly, POP inhibition was recently shown to increase PP2A activity, thereby reducing oxidative stress [ 39 , 40 ]. Moreover, PP2A serves an important role in protection against renal inflammation [ 41 ]. To demonstrate whether PP2A is also activated (i.e., dephosphorylated) by KYP2047 during KI/R, the activated form of PP2A, and the inactivated form (pPP2A) were measured in kidney samples, showing as KYP2047 treatment significantly increased PP2A and reduced pPP2A (respectively, Figure 8 A,B).…”

Section: Resultsmentioning

confidence: 99%

“…It is known that PP2A serves an important role in protection against renal inflammation [ 41 ] and the developmental regulation of PP2A activity and protein during kidney growth suggests a role for PP2A in the regulation of nephron differentiation [ 66 ]. For the first time, in this study, the involvement of PP2A was demonstrated in renal ischemia/reperfusion injury, suggesting an important connection between POP-inhibition and PP2A activity, and strengthening the anti-inflammatory mechanisms of KYP2047 treatment through PP2A activation.…”

Section: Discussionmentioning

confidence: 99%

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The Protective Role of Prolyl Oligopeptidase (POP) Inhibition in Kidney Injury Induced by Renal Ischemia–Reperfusion

Casili

Ardizzone

Basilotta

et al. 2021

IJMS

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Ischemia/reperfusion injury (IRI) is a complex pathophysiological process characterized by blood circulation disorder caused by various factors, such as traumatic shock, surgery, organ transplantation, and thrombus. Severe metabolic dysregulation and tissue structure destruction are observed upon restoration of blood flow to the ischemic tissue. The kidney is a highly perfused organ, sensitive to ischemia and reperfusion injury, and the incidence of renal IRI has high morbidity and mortality. Several studies showed that infiltration of inflammatory cells, apoptosis, and angiogenesis are important mechanisms involved in renal IRI. Despite advances in research, effective therapies for renal IRI are lacking. Recently it has been demonstrated the role of KYP2047, a selective inhibitor of prolyl oligopeptidase (POP), in the regulation of inflammation, apoptosis, and angiogenesis. Thus, this research focused on the role of POP in kidney ischemia/reperfusion (KI/R). An in vivo model of KI/R was performed and mice were subjected to KYP2047 treatment (intraperitoneal, 0.5, 1 and 5 mg/kg). Histological analysis, Masson’s trichrome and periodic acid shift (PAS) staining, immunohistochemical and Western blots analysis, real-time PCR (RT-PCR) and ELISA were performed on kidney samples. Moreover, serum creatinine and blood urea nitrogen (BUN) were quantified. POP-inhibition by KYP2047 treatment, only at the doses of 1 and 5 mg/kg, significantly reduced renal injury and collagen amount, regulated inflammation through canonical and non-canonical NF-κB pathway, and restored renal function. Moreover, KYP2047 modulated angiogenesis markers, such as TGF-β and VEGF, also slowing down apoptosis. Interestingly, treatment with KYP2047 modulated PP2A activity. Thus, these findings clarified the role of POP inhibition in AKI, also offering novel therapeutic target for renal injury after KI/R.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Protective Role of Prolyl Oligopeptidase (POP) Inhibition in Kidney Injury Induced by Renal Ischemia–Reperfusion

Casili

Ardizzone

Basilotta

et al. 2021

IJMS

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“…This heightened expression of PP2Ac in patients with SLE plays a substantial anti-inflammatory role in renal tissues 26 and is also found to enhance the stability of podocytes. 27 This increased serum level of PP2A regulatory subunit (IGBP1) in LN may contribute to understanding the histological podocyte injury observed in various LN classes. 28,29 Unlike the most severe classes of LN (classes III and IV) that are associated with anti-dsDNA antibodies that induce complement activation and inflammatory reactions, 30 membranous LN (class V) is characterized by subepithelial deposits, leading to local complement activation and more pronounced podocyte dysfunction, typically with little or no inflammatory reaction.…”

Section: Discussionmentioning

confidence: 99%

Validity of immunoglobulin-binding protein 1 as a biomarker for lupus nephritis

Ebaid

Ezzeldin

Abdelhady

et al. 2022

Lupus

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Background Lupus nephritis (LN) is a major issue that adds a burden on patients with systemic lupus erythematosus (SLE). Immunoglobulin-binding protein 1 (IGBP1) is identified as a phosphoprotein that has been recently reported to be linked to the B-cell receptor complex and regulates differentiation, proliferation, apoptosis, and tolerance of B cells. Its diagnostic and/or prognostic role in LN has been highlighted only recently. Objectives This study aims to evaluate the relation between serum IGBP1 and SLE disease activity and/or renal activity and to investigate the validity of IGBP1 as a biomarker for LN. Methods 96 participants were enrolled and divided into three groups: nephritis, nonnephritis, and control groups. The patients with SLE were diagnosed according to the Systemic Lupus International Collaborating Clinics classification (SLICC) criteria. The serum IGBP1 level was assayed using an enzyme-linked immunosorbent assay (ELISA). Assessments were conducted using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2k) and renal biopsy for LN patients. Results The nephritis and nonnephritis groups had higher IGBP1 levels than the controls; the nephritis group had the highest serum IGBP1 levels ( p < .001). Significant correlations were found between IGBP1 levels and proteinuria (r = 0.568, p = .001) and renal SLEDAI (r = 0.475, p = .006) in the nephritis group; on the other hand, the correlation of serum IGBP1 levels with SLEDAI-2K was non-significant for both groups (nephritis and nonnephritis groups). The IGBP1 levels were significantly different among histopathologic classes ( p < .001), with class V showing the highest level. Moreover, it showed a significant positive correlation with the pathologic activity index. Compared with renal SLEDAI for identifying active renal affection in patients with SLE, the serum IGBP1 level with a cut-off value of 547.45 ng/mL is a valid biomarker for detecting active nephritis with 93.8% sensitivity and 96.9% specificity. Conclusion The serum IGBP1 levels were high in patients with LN and were positively correlated with the pathologic activity index. The serum IGBP1 level of 547.45 ng/mL is a valid biomarker for detecting active nephritis. Thus, we recommend that clinicians monitor the serum IGBP1 level of patients with SLE to detect LN.

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“…Deregulation of these processes is likely to have major functional implications since TJs and epithelial polarity play a critical role in kidney homeostasis, and the kidney is an important site for one-carbon metabolism ( Ducker and Rabinowitz, 2017 ). Indeed, disturbances in one-carbon metabolism ( Karmin and Siow, 2018 ), deregulation of PP2A ( Shao et al, 2021 ) and TJ dysfunction ( Denker and Sabath, 2011 ; Szaszi and Amoozadeh, 2014 ; Bhat et al, 2018 ) are all linked to various kidney diseases, including carcinomas.…”

Section: Discussionmentioning

confidence: 99%

A Novel Role of PP2A Methylation in the Regulation of Tight Junction Assembly and Integrity

Schuhmacher

Sontag

2022

Front. Cell Dev. Biol.

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Tight junctions (TJs) are multiprotein complexes essential for cell polarity and the barrier function of epithelia. The major signaling molecule, protein serine/threonine phosphatase 2A (PP2A), interacts with the TJ and modulates the phosphorylation state of TJ proteins. An important PP2A regulatory mechanism involves leucine carboxyl methyltransferase-1 (LCMT1)-dependent methylation and protein phosphatase methylesterase-1 (PME1)-mediated demethylation of its catalytic subunit on Leu309. Here, using MDCK cells, we show that overexpression of LCMT1, which enhances cellular PP2A methylation, inhibits TJ formation, induces TJ ruffling, and decreases TJ barrier function. Conversely, overexpression of PME1 accelerates TJ assembly and enhances TJ barrier function. PME1-dependent PP2A demethylation increases during early Ca2+-dependent junctional assembly. Inhibition of endogenous PME1 delays the initial Ca2+-mediated redistribution of TJ proteins to cell-cell contacts and affects TJ morphology and barrier function. Manipulating one-carbon metabolism modulates TJ assembly, at least in part by affecting PP2A methylation state. The integrity of PP2A methylation is critical for proper targeting of PP2A to the TJ. It is necessary for PP2A complex formation with the TJ proteins, occludin and ZO-1, and proteins of the PAR complex, Par3 and atypical protein kinase C ζ (aPKCζ), which play a key role in development of cell polarity. Expression of a methylation incompetent PP2A mutant induces defects in TJ assembly and barrier function. aPKCζ-mediated Par3 phosphorylation is also required for targeting of the PP2A ABαC holoenzyme to the TJ. Our findings provide the first evidence for a role of LCMT1, PME1 and PP2A methylation/demethylation processes in modulating TJ assembly and functional integrity. They also position PP2A at the interface of one-carbon metabolism and the regulation of key TJ and polarity proteins that become deregulated in many human diseases.

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Role of protein phosphatase 2A in kidney disease (Review)

Cited by 9 publications

References 126 publications

The Protective Role of Prolyl Oligopeptidase (POP) Inhibition in Kidney Injury Induced by Renal Ischemia–Reperfusion

The Protective Role of Prolyl Oligopeptidase (POP) Inhibition in Kidney Injury Induced by Renal Ischemia–Reperfusion

Validity of immunoglobulin-binding protein 1 as a biomarker for lupus nephritis

A Novel Role of PP2A Methylation in the Regulation of Tight Junction Assembly and Integrity

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