scholarly journals Role of tubular epithelial arginase-II in renal inflammaging

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ji Huang ◽  
Xiujie Liang ◽  
Diogo Ladeiras ◽  
Benoit Fellay ◽  
Xiu-Fen Ming ◽  
...  
Keyword(s):  
Aging Process ◽  
Kidney Diseases ◽  
Treatment And Prevention ◽  
Promising Therapeutic Target ◽  
Proximal Tubular ◽  
Arginase Ii ◽  
Renal Proximal Tubular ◽  
Renal Aging ◽  
Aging Kidney

AbstractThe aging kidney undergoes complex changes and is vulnerable to injury and development of chronic kidney disease (CKD) with preponderance affecting more women than men. Evidence has been presented that the type-II L-arginine:ureohydrolase, arginase-II (Arg-II) plays a role in the acceleration of aging. Arg-II is highly expressed in the kidney. However, the role of Arg-II in renal aging is not known. This study is to investigate whether Arg-II is involved in the kidney aging process dependently on sex. Arg-II level in the kidney of wild type (WT) mice is significantly elevated with aging, which is accompanied by an increase in expression of the inflammatory cytokines/chemokines, tissue macrophages, factors involved in fibrosis, and tubulointestitial fibrosis in both males and females. This renal aging phenotype is significantly suppressed in arg-II−/− mice, mainly in the females in which Arg-II level is higher than in the males. Importantly, numerous factors such as IL-1β, MCP1, VCAM-1, and TGFβ1 are mainly localized in the proximal tubular S3 segment cells expressing Arg-II in the aging kidney. In human proximal tubular cells (HK-2), TNF-α enhances adhesion molecule expression dependently on Arg-II upregulation. Overexpression of Arg-II in the cells enhances TGFβ1 levels which is prevented by mitochondrial ROS inhibition. In summary, our study reveals that renal proximal tubular Arg-II plays an important role in the kidney aging process in females. Arg-II could be a promising therapeutic target for the treatment and prevention of aging-associated kidney diseases.

scholarly journals Upregulation of soluble epoxide hydrolase in proximal tubular cells mediated proteinuria-induced renal damage

2013 ◽  
Vol 304 (2) ◽  
pp. F168-F176 ◽  
Author(s):  
Qian Wang ◽  
Wei Pang ◽  
Zhuan Cui ◽  
Junbao Shi ◽  
Yan Liu ◽  
...  
Keyword(s):  
Serum Albumin ◽  
Epoxide Hydrolase ◽  
Renal Damage ◽  
Kidney Diseases ◽  
Soluble Epoxide Hydrolase ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular

Epoxyeicosatrienoic acids, hydrolyzed by soluble epoxide hydrolase (sEH), have multiple biological functions, including the regulation of vascular tone, renal tubular transport, and being anti-inflammatory. Inhibitors of sEH have been demonstrated to be antihypertensive and renal protective. To elucidate the role of sEH in glomerulonephritis, we first determined the expression of sEH in human kidney by examining biopsies from 153 patients with a variety of glomerulonephritis, including minimal-change, membranous, and IgA nephropathy. Immunohistochemical staining of frozen kidney biopsy samples revealed sEH preferentially expressed in the renal proximal tubular cells, and its expression increased in all patients with glomerulonephritis. The level of sEH in the cortex was positively correlated with proteinuria and negatively with serum albumin level. To investigate the role of sEH in proteinuria-induced renal damage, we incubated purified urine protein from patients with rat renal proximal tubular epithelial cells in vitro. The level of sEH was elevated, as were monocyte chemoattractant protein 1 and the process of tubular epithelial-to-mesenchymal transition, characterized with increased α-smooth muscle actin (α-SMA) and decreased E-cadherin. These effects were attenuated by administration of a potent sEH inhibitor and mimicked with adenovirus-mediated sEH overexpression. In adriamycin-induced nephropathic mice, sEH inhibitor did not ameliorate proteinuria or level of serum albumin but reduced the long-term elevated serum creatinine level, interstitial inflammation, fibrosis, and α-SMA expression. Thus upregulation of sEH in proximal tubular cells in chronic proteinuric kidney diseases may mediate proteinuria-induced renal damage; sEH inhibition by increasing renal eicosanoid levels could prevent the progression of chronic proteinuric kidney diseases.

scholarly journals Aristolochic Acid Induces Renal Fibrosis and Senescence in Mice

2021 ◽  
Vol 22 (22) ◽  
pp. 12432
Author(s):  
Shingo Urate ◽  
Hiromichi Wakui ◽  
Kengo Azushima ◽  
Takahiro Yamaji ◽  
Toru Suzuki ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Aristolochic Acid ◽  
Kidney Diseases ◽  
Functional Decline ◽  
Related Factors ◽  
Chronic Kidney Diseases ◽  
Age Related ◽  
Proximal Tubular ◽  
Renal Aging ◽  
Aging Kidney

The kidney is one of the most susceptible organs to age-related impairments. Generally, renal aging is accompanied by renal fibrosis, which is the final common pathway of chronic kidney diseases. Aristolochic acid (AA), a nephrotoxic agent, causes AA nephropathy (AAN), which is characterized by progressive renal fibrosis and functional decline. Although renal fibrosis is associated with renal aging, whether AA induces renal aging remains unclear. The aim of the present study is to investigate the potential use of AAN as a model of renal aging. Here, we examined senescence-related factors in AAN models by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group demonstrated aging kidney phenotypes, such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidneys, and increased renal p16 mRNA expression and senescence-associated β-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, as well as reactive oxygen species accumulation. Klotho, an antiaging gene, was also significantly decreased in the kidneys of AA-treated mice. Collectively, the results of the present study indicate that AA alters senescence-related factors, and that renal fibrosis is closely related to renal aging.

Is there a role of cyclosporine A on total homocysteine export from human renal proximal tubular epithelial cells?

2001 ◽  
Vol 59 (s78) ◽  
pp. 258-261 ◽  
Author(s):  
Mihaela C. Ignatescu ◽  
Manuela Fodiger ◽  
Josef Kletzmayr ◽  
Christian Bieglmayer ◽  
Walter H. Horl ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cyclosporine A ◽  
Tubular Epithelial Cells ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Total Homocysteine ◽  
Renal Proximal Tubular

scholarly journals The role of cysteine proteases in hypoxia-induced rat renal proximal tubular injury.

1995 ◽  
Vol 92 (17) ◽  
pp. 7662-7666 ◽  
Author(s):  
C. L. Edelstein ◽  
E. D. Wieder ◽  
M. M. Yaqoob ◽  
P. E. Gengaro ◽  
T. J. Burke ◽  
...  
Keyword(s):  
Cysteine Proteases ◽  
Tubular Injury ◽  
Proximal Tubular ◽  
Renal Proximal Tubular

scholarly journals Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage

2020 ◽  
Vol 11 ◽  
Author(s):  
Rossana Franzin ◽  
Alessandra Stasi ◽  
Marco Fiorentino ◽  
Giovanni Stallone ◽  
Vincenzo Cantaluppi ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Complement System ◽  
Kidney Diseases ◽  
Critical Role ◽  
Graft Function ◽  
Kidney Injury ◽  
Increased Risk ◽  
Wide Range ◽  
Renal Aging

The aberrant activation of complement system in several kidney diseases suggests that this pillar of innate immunity has a critical role in the pathophysiology of renal damage of different etiologies. A growing body of experimental evidence indicates that complement activation contributes to the pathogenesis of acute kidney injury (AKI) such as delayed graft function (DGF) in transplant patients. AKI is characterized by the rapid loss of the kidney’s excretory function and is a complex syndrome currently lacking a specific medical treatment to arrest or attenuate progression in chronic kidney disease (CKD). Recent evidence suggests that independently from the initial trigger (i.e., sepsis or ischemia/reperfusions injury), an episode of AKI is strongly associated with an increased risk of subsequent CKD. The AKI-to-CKD transition may involve a wide range of mechanisms including scar-forming myofibroblasts generated from different sources, microvascular rarefaction, mitochondrial dysfunction, or cell cycle arrest by the involvement of epigenetic, gene, and protein alterations leading to common final signaling pathways [i.e., transforming growth factor beta (TGF-β), p16ink4a, Wnt/β-catenin pathway] involved in renal aging. Research in recent years has revealed that several stressors or complications such as rejection after renal transplantation can lead to accelerated renal aging with detrimental effects with the establishment of chronic proinflammatory cellular phenotypes within the kidney. Despite a greater understanding of these mechanisms, the role of complement system in the context of the AKI-to-CKD transition and renal inflammaging is still poorly explored. The purpose of this review is to summarize recent findings describing the role of complement in AKI-to-CKD transition. We will also address how and when complement inhibitors might be used to prevent AKI and CKD progression, therefore improving graft function.

Gentamicin inhibits rat renal cortical homotypic endosomal fusion: role of megalin

1997 ◽  
Vol 272 (1) ◽  
pp. F117-F123 ◽  
Author(s):  
T. G. Hammond ◽  
R. R. Majewski ◽  
J. H. Kaysen ◽  
F. O. Goda ◽  
G. L. Navar ◽  
...  
Keyword(s):  
Damage Mechanism ◽  
Repeat Sequence ◽  
Sequence Motifs ◽  
Polyaspartic Acid ◽  
In Vitro Reconstitution ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

Megalin, a giant glycoprotein receptor heavily concentrated in the early endosomal pathway of renal proximal tubular cells, binds gentamicin with high affinity and delivers the drug to lysosomes. Utilizing an in vitro reconstitution assay we tested whether gentamicin-induced vacuolation is associated with inhibition of early endosomal fusion, as well as whether megalin plays a role in mediating these effects. Pretreatment of rats with gentamicin inhibited rat renal proximal tubular homotypic endosomal fusion. Administered simultaneously, gentamicin and polymers of polyaspartic acid, which protect against the hemodynamic effects of gentamicin nephrotoxicity, had no net effect on fusion. Polyaspartic acid alone had no effect on fusion. Antisera to the tail of the megalin/gentamicin receptor inhibited fusion, whereas non-specific controls had no effect. Peptides matching homologous NPXY repeat sequence motifs in the cytosolic tail stimulated endosomal fusion, whereas reverse sequence control peptides had no effect. These data suggest that gentamicin inhibition of endosomal fusion in the renal proximal tubule is a damage mechanism mediated by specific peptide sequences in the cytosolic tail of the giant gentamicin-binding receptor megalin and that receptors can effect the fusion properties of membranes in which they reside.

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