MO263KLOTHO IS PROTECTIVE IN THE CONTEXT OF ACUTE GLOMERULAR INJURY BUT IS NOT EXPRESSED IN PODOCYTES

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Emmanuelle Charrin ◽  
Dina Dabaghie ◽  
Rik Mencke ◽  
Ilke Sen ◽  
Katja Möller-Hackbarth ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Tubular Damage ◽  
Protective Effects ◽  
Glomerular Injury ◽  
Protein Levels ◽  
Filtration Barrier ◽  
Renal Histology ◽  
Distant Organ ◽  
Health And Disease ◽  
And Function

Abstract Background and Aims Podocyte integrity is crucial for the maintenance of glomerular function in health and disease. Numerous studies have reported that Klotho overexpression, or treatment with recombinant Klotho, reduces glomerular and tubular damage in mouse models of renal disease. However, the mechanism(s) of action are not fully understood. Several recent studies have also reported that Klotho is expressed in podocytes, where it protects against various types of injury. These findings conflict with previous studies, which have shown that renal Klotho expression is exclusively confined to proximal and distal tubular cells. Method To address this discrepancy and enhance our understanding of the putative glomeruloprotective effects mediated by Klotho, we examined the expression pattern of Klotho in human and mouse kidney by several different methods, and explored its protective effects by overexpressing full-length human Klotho directly in podocytes or in a distant organ (i.e. liver). Results Data at the mRNA and protein levels all converged towards an absence or very low expression of Klotho in podocytes. The generation of a podocyte-specific Klotho knockout mouse further demonstrated that its deletion did not affect glomerular structure or function. Moreover, Klotho deficiency did not worsen glomerular injury in an experimental model of glomerulonephritis (anti-GBM). However, when Klotho was overexpressed in hepatocytes (Alb-cre;hKlothofl/+ - Alb-hKL), serum Klotho increased drastically with no changes in Fgf23 or phosphate metabolism. In mice challenged with anti-GBM, renal histology and ultrastructure of the filtration barrier was less severely affected in Alb-hKL compared to WT mice. There were also significantly less albuminuria, podocyte loss and interstitial fibrosis in Alb-hKL mice compared to their WT littermates. In contrast, mice which overexpressed Klotho in podocytes (Pod-hKL) were not protected from renal injury. Conclusion Taken together, these results strongly suggest that Klotho is not expressed in any substantial amounts in human or mouse podocytes, and that membrane-bound Klotho does not play a role in podocyte biology. Importantly, our results confirm a beneficial role for soluble Klotho in protecting podocytes against injury, and in maintaining glomerular integrity and function.

scholarly journals miR-125a-5p: a novel regulator of SLC26A6 expression in intestinal epithelial cells

2019 ◽  
Vol 317 (2) ◽  
pp. C200-C208 ◽  
Author(s):  
Arivarasu N. Anbazhagan ◽  
Shubha Priyamvada ◽  
Alip Borthakur ◽  
Seema Saksena ◽  
Ravinder K. Gill ◽  
...  
Keyword(s):  
Untranslated Region ◽  
In Silico Analysis ◽  
Luciferase Reporter ◽  
Intestinal Epithelial ◽  
Protein Levels ◽  
Anion Transporter ◽  
Oxalate Secretion ◽  
Recent Emergence ◽  
Health And Disease ◽  
And Function

Putative anion transporter 1 (PAT1, SLC26A6), an intestinal epithelial Cl−/[Formula: see text] exchanger, also plays a key role in oxalate homeostasis via mediating intestinal oxalate secretion. Indeed, Slc26a6-null mice showed defect in intestinal oxalate secretion and high incidence of kidney stones. Recent emergence of PAT-1 as a novel therapeutic target for nephrolithiasis warrants detailed understanding of the mechanisms of PAT-1 regulation in health and disease. Therefore, we investigated the regulation of PAT-1 expression by microRNAs (miRNA), as they have been shown to play key role in modulating expression of other ion transporters. In silico analysis of PAT-1 3′-untranslated region (UTR) revealed potential binding sites for several miRNAs, suggesting the role of miRNAs in modulating PAT1 expression. miRNAs showing highest context scores (125a-5p, 339-5p, 423-5p, 485-5p, and 501-3p) were selected as candidates for their effects on the activity of a 263-bp PAT-1 3′-untranslated region (UTR) fragment cloned into pmirGLO vector upstream of luciferase. The 3′-UTR activity was measured by dual luciferase reporter assay in Caco-2, T-84, HT-29, and SK-CO15 cells. Transient transfection of PAT-1 3′-UTR significantly decreased the relative luciferase activity compared with the empty vector suggesting binding of potential miRNA(s) to the PAT-1 3′-UTR. Among all the selected candidates, cotransfection with miRNA mimics 125a-5p and 423-5p further decreased PAT-1 3′-UTR activity. Furthermore, increasing miR-125a-5p abundance via mimic transfection in Caco-2 cells decreased both mRNA and protein levels of PAT-1. Our results demonstrate a novel regulatory mechanism of intestinal PAT-1 expression via miR-125a-5p that could be of therapeutic importance in disorders associated with decreased PAT-1 expression and function.

scholarly journals Brain Mineralocorticoid receptor in health and disease: from molecular signaling to cognitive and emotional function

2021 ◽  
Author(s):  
Susana Paul ◽  
Katja Wingenfeld ◽  
Christian Otte ◽  
Onno Meijer
Keyword(s):  
Mineralocorticoid Receptor ◽  
Psychiatric Symptoms ◽  
Stress Hormones ◽  
Affective State ◽  
Protective Effects ◽  
Molecular Signaling ◽  
Pharmacological Interventions ◽  
Mediated Effects ◽  
Health And Disease ◽  
And Function

Brain mineralocorticoid receptors (MR) mediate effects of aldosterone in relation to salt homeostasis, and of glucocorticoid stress hormones corticosteroids in the context of stress adaptation. Brain stem MRs respond to aldosterone, while forebrain MRs mediate rapid and delayed MR-mediated glucocorticoids effects in conjunction with the glucocorticoid receptor. MR-mediated effects depend on gender, genetic variations and environmental influences. Disturbed MR activity by chronic stress or in certain (endocrine) diseases can cause deleterious effects on affective state, cognitive and behavioural function in susceptible individuals. High MR activation may have protective effects in healthy individuals, whereas dysregulated high MR activity during a stress response would require treatment with mineralocorticoid receptor antagonists (MRAs). Here, we discuss recent pharmacological and genetic developments, from the molecular underpinnings of MR signaling and function, to pharmacological interventions in the clinic. Improved understanding of MR dependent pathways will help to improve glucocorticoid therapy, unwanted side effects and psychiatric symptoms.

Role of macrophages in the fibrotic phase of rat crescentic glomerulonephritis

2013 ◽  
Vol 304 (8) ◽  
pp. F1043-F1053 ◽  
Author(s):  
Yingjie Han ◽  
Frank Y. Ma ◽  
Greg H. Tesch ◽  
Carl L. Manthey ◽  
David J. Nikolic-Paterson
Keyword(s):  
Renal Dysfunction ◽  
Crescentic Glomerulonephritis ◽  
Kinase Inhibitor ◽  
Interstitial Fibrosis ◽  
Macrophage Infiltration ◽  
Tubular Damage ◽  
Glomerular Injury ◽  
T Cell Infiltration ◽  
Wistar Kyoto

The ability of macrophages to cause acute inflammatory glomerular injury is well-established; however, the role of macrophages in the fibrotic phase of chronic kidney disease remains poorly understood. This study examined the role of macrophages in the fibrotic phase ( days 14 to 35) of established crescentic glomerulonephritis. Nephrotoxic serum nephritis (NTN) was induced in groups of eight Wistar-Kyoto rats that were given a selective c-fms kinase inhibitor, fms-I, or vehicle alone from day 14 until being killed on day 35. Rats killed on day 14 NTN had pronounced macrophage infiltration with glomerular damage, fibrocellular crescents in 50% of glomeruli, tubulointerstitial damage, heavy proteinuria, and renal dysfunction. Glomerulosclerosis was more severe by day 35 in vehicle-treated rats, as was periglomerular and interstitial fibrosis, while proteinuria and renal dysfunction continued unabated and some parameters of tubular damage worsened. During the day 14-to- 35 period, glomerular and interstitial macrophage infiltration decreased with an apparent change from a proinflammatory M1 phenotype to an alternatively activated M2 phenotype. Treatment with fms-I over days 14 to 35 selectively reduced blood monocyte numbers and abrogated glomerular and interstitial macrophage infiltration. This resulted in improved renal function, significantly reduced glomerular and interstitial fibrosis, and protection against further peritubular capillary loss. However, sustained proteinuria, tubular damage, and interstitial T cell infiltration and activation were unaffected. In conclusion, this study demonstrates that macrophages contribute to renal dysfunction and tissue damage in established crescentic glomerulonephritis as it progresses from the acute inflammatory to a chronic fibrotic phase.

scholarly journals Matrix Metalloproteinase 9 Protects Mice from Anti–Glomerular Basement Membrane Nephritis through Its Fibrinolytic Activity

2001 ◽  
Vol 193 (7) ◽  
pp. 793-802 ◽  
Author(s):  
Brigitte Lelongt ◽  
Soraya Bengatta ◽  
Madeleine Delauche ◽  
Leif R. Lund ◽  
Zena Werb ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Matrix Metalloproteinase ◽  
Glomerular Basement Membrane ◽  
Glomerular Injury ◽  
Important Mediator ◽  
Renal Histology ◽  
Glomerular Lesions ◽  
And Function ◽  
Old Mice ◽  
Metalloproteinase 9

Matrix metalloproteinase (MMP)9/gelatinase B is increased in various nephropathies. To investigate its role, we used a genetic approach. Adult MMP9-deficient (MMP9−/−) mice showed normal renal histology and function at 3 mo. We investigated the susceptibility of 3-mo-old mice to the accelerated model of anti-glomerular basement membrane nephritis, in which fibrin is an important mediator of glomerular injury and renal impairment. Unexpectedly, nephritis was more severe in MMP9−/− than in control mice, as attested by levels of serum creatinine and albuminuria, and the extent of crescents and fibrin deposits. Circulating or deposited immunoglobulin G, interleukin (IL)-1β, or IL-10 were the same in MMP9−/− and MMP9+/+ mice. However, we found that fibrin is a critical substrate for MMP9, and in its absence fibrin accumulated in the glomeruli. These data indicate that MMP9 is required for a novel protective effect on the development of fibrin-induced glomerular lesions.

Rofecoxib decreases renal injury in obese Zucker rats

2004 ◽  
Vol 107 (6) ◽  
pp. 561-570 ◽  
Author(s):  
Aparajita DEY ◽  
Christine MARIC ◽  
Wayne H. KAESEMEYER ◽  
Constantine Z. ZAHARIS ◽  
Janet STEWART ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Renal Injury ◽  
Renal Damage ◽  
Interstitial Fibrosis ◽  
Zucker Rats ◽  
Glomerular Injury ◽  
Protein Levels ◽  
Vascular Regulation ◽  
Obese Zucker Rats ◽  
Cox 2

The present study tested the hypothesis that altered vascular regulation of arachidonic acid enzymes in obese Zucker rats contributes to renal damage. Protein expression of CYP450 (cytochrome P450) and COX (cyclo-oxygenase) enzymes in renal microvessels was studied in obese and lean Zucker rats at 20–21 weeks of age. Body weight and blood glucose averaged 649±13 g and 142±10 mg/dl in obese Zucker rats compared with 437±10 g and 111±5 mg/dl in age-matched lean Zucker rats. Renal microvascular CYP4A and COX-2 protein levels were increased and CYP2C protein levels decreased in obese Zucker rats. TX (thromboxane) B2 excretion was 2-fold higher and PG (prostaglandin) E2 excretion significantly lower in obese Zucker rats. Additional studies investigated the ability of the COX-2 inhibitor, rofecoxib, to slow the progression of renal injury in obese Zucker rats. Rofecoxib treatment decreased urinary PGF2α and 8-isoprostane levels in obese Zucker rats. Renal microvessel mRNA expression of pro-inflammatory chemokines was decreased in COX-2-inhibitor-treated obese Zucker rats. Urinary albumin excretion, an index of kidney damage, averaged 95±11 mg/day in vehicle-treated and 9±1 mg/day in rofecoxib-treated obese Zucker rats. Glomerulosclerosis, characterized by mesangial expansion, tubulo-interstitial fibrosis and extracellular matrix accumulation, was prominent in obese Zucker rats compared with a lack of damage in age-matched lean Zucker rats and rofecoxib-treated obese Zucker rats. These results suggest that altered vascular arachidonic acid enzymes contribute to the renal damage, and that COX-2 inhibition decreases glomerular injury in obese Zucker rats.

Abstract 78: TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3 and NF-kB Dependent Activation of OPA1 Expression

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Jing-Liang Nan ◽  
Wei Zhu ◽  
Ying-Chao Wang ◽  
Zhi-Wei Zhong ◽  
Lian-lian Zhu ◽  
...  
Keyword(s):  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Protective Effects ◽  
Promoter Regions ◽  
Neonatal Cardiomyocytes ◽  
Protein Levels ◽  
Dynamic Simulation Model ◽  
Underlying Mechanisms ◽  
Reported Data ◽  
And Function

Background: TNFR2 stimulation is known to possess protective effects for the cardiomyocytes, however, the underlying mechanisms remain unknown. Methods and Results: Using cultured neonatal cardiomyocytes that were infected with lentivirus containing shRNA targeting TNFR1, we showed that TNFR2 activation by TNFα (5nmol/L) resulted in increased mitochondrial fusion, mitochondrial membrane potential which were associated with both elevated intracellular ATP levels and oxygen consumption rate. Intriguingly, these changes were associated with increased protein levels of OPA1, with no changes in the expression levels of Drp1, Mfn1, Mfn2. We went further and reproduced previously reported data that NF-kB acetylation (Lys310) was increased with TNFR2 activation. Interestingly, however, we also observed dose-dependent effects on increase in Stat3 acetylation. Using shRNA approach, we then demonstrated that either Stat3 or NF-kB knockdown can attenuate TNFR2 induced OPA1 expression. The close interaction between these two signalings was validated by co-IP assay and confocal immunofluorescence staining. Aided by bio-informatics searching, we then performed ChIP assay to show that the binding sites of OPA1 promoter regions for STAT3 (-156 to -167) and NFkB (-192 to -203) were adjacent. We further validated that p300 induced Stat3 acetylation was indispensable for complex formation by the interaction between Stat3-DBD and NF-kB -ΔRHD, which in turn was a key event for OPA1 transcription activation. And silence of p300 can abolish OPA1 upregulation upon TNFR2 activation. Computerized data analysis based on zdock and zrank score followed by molecular dynamic simulation model for the whole Stat3 structure revealed higher value of the exterior dielectric constant (obtained from MM/PBSA calculation) for the two sites, K370 and K383, of Stat3, suggesting the essential roles for these two sites for Stat3-NFkB interaction, which were confirmed by co-IP with Stat3-DBD mutants (K370Q,K370R,K383Q,K383R) approach. Conclusions: Our data suggested that p300 mediated Stat3 acetylation cooperates with NF-kB to modulate TNFR2 activation induced OPA1 upregulation, leading to improved mitochondrial morphology and function.

Genetic background determines renal response to chronic lithium treatment in female mice

2021 ◽  
Author(s):  
Theun de Groot ◽  
Rosalinda Doty ◽  
Lars Damen ◽  
Ruben Baumgarten ◽  
Steffi Bressers ◽  
...  
Keyword(s):  
Genetic Background ◽  
Interstitial Fibrosis ◽  
Lithium Treatment ◽  
Renal Pathology ◽  
Glomerular Injury ◽  
Duration Of Treatment ◽  
Tubular Atrophy ◽  
Female Mice ◽  
Renal Histology ◽  
Urine Production

Background Chronic lithium treatment for bipolar disease causes mainly side effects in the kidney. A subset of lithium users develops nephrogenic diabetes insipidus (NDI), a urinary concentrating disorder, and chronic kidney disease (CKD). Age, lithium dose and duration of treatment are important risk factors, while genetic background might also play an important role. Methods In order to investigate the role of genetics, female mice of 29 different inbred strains were treated for one year with control or lithium chow and urine, blood and kidneys were analysed. Results Chronic lithium treatment increased urine production and/or reduced urine osmolality in 21 strains. Renal histology showed that lithium increased interstitial fibrosis and/or tubular atrophy in eight strains, while in none of the strains glomerular injury was induced. Interestingly, lithium did not elevate urinary albumin-creatinine ratio (ACR) in any strain, while eight strains even demonstrated a lowered ACR. The protective effect on ACR coincided with a similar decrease in urinary IgG levels, a marker of glomerular function, while the adverse effect of lithium on interstitial fibrosis/tubular atrophy coincided with a severe increase in urinary β2-microglobulin (B2M) levels, an indicator of proximal tubule damage. Conclusion Genetic background plays an important role in the development of lithium-induced NDI and chronic renal pathology in female mice. The strong correlation of renal pathology with urinary B2M levels indicates B2M as a promising biomarker for chronic renal damage induced by lithium.

The podocyte in health and disease: insights from the mouse

2007 ◽  
Vol 112 (6) ◽  
pp. 325-335 ◽  
Author(s):  
Jean-Louis R. Michaud ◽  
Chris R. J. Kennedy
Keyword(s):  
Glomerular Filtration ◽  
Genetic Manipulation ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Form And Function ◽  
Filtration Barrier ◽  
Scientific Disciplines ◽  
Fenestrated Endothelium ◽  
Health And Disease ◽  
And Function

The glomerular filtration barrier consists of the fenestrated endothelium, the glomerular basement membrane and the terminally differentiated visceral epithelial cells known as podocytes. It is now widely accepted that damage to, or originating within, the podocytes is a key event that initiates progression towards sclerosis in many glomerular diseases. A wide variety of strategies have been employed by investigators from many scientific disciplines to study the podocyte. Although invaluable insights have accrued from conventional approaches, including cell culture and biochemical-based methods, many renal researchers continue to rely upon the mouse to address the form and function of the podocyte. This review summarizes how genetic manipulation in the mouse has advanced our understanding of the podocyte in relation to the maintenance of the glomerular filtration barrier in health and disease.

scholarly journals Insights into the Functional Role of ADTRP (Androgen-Dependent TFPI-Regulating Protein) in Health and Disease

2021 ◽  
Vol 22 (9) ◽  
pp. 4451
Author(s):  
Cristina Lupu ◽  
Maulin M. Patel ◽  
Florea Lupu
Keyword(s):  
Tissue Factor ◽  
Critical Role ◽  
Fatty Acid Esters ◽  
Protective Effects ◽  
Nucleotide Polymorphisms ◽  
Vein Thrombosis ◽  
Health And Disease ◽  
Vessel Integrity ◽  
And Function

The novel protein ADTRP, identified and described by us in 2011, is androgen-inducible and regulates the expression and activity of Tissue Factor Pathway Inhibitor, the major inhibitor of the Tissue Factor-dependent pathway of coagulation on endothelial cells. Single-nucleotide polymorphisms in ADTRP associate with coronary artery disease and myocardial infarction, and deep vein thrombosis/venous thromboembolism. Some athero-protective effects of androgen could exert through up-regulation of ADTRP expression. We discovered a critical role of ADTRP in vascular development and vessel integrity and function, manifested through Wnt signaling-dependent regulation of matrix metalloproteinase-9. ADTRP also hydrolyses fatty acid esters of hydroxy-fatty acids, which have anti-diabetic and anti-inflammatory effects and can control metabolic disorders. Here we summarize and analyze the knowledge on ADTRP and try to decipher its functions in health and disease.

scholarly journals Increased Renal Angiopoietin-1 Expression in Folic Acid-Induced Nephrotoxicity in Mice

2001 ◽  
Vol 12 (12) ◽  
pp. 2721-2731 ◽  
Author(s):  
David A. Long ◽  
Adrian S. Woolf ◽  
Toshio Suda ◽  
Hai T. Yuan
Keyword(s):  
Folic Acid ◽  
Growth Factors ◽  
Interstitial Fibrosis ◽  
Periodic Acid ◽  
Nuclear Antigen ◽  
Tubular Damage ◽  
Periodic Acid Schiff ◽  
Protein Levels ◽  
Epithelial Regeneration ◽  
Platelet Endothelial Cell Adhesion

ABSTRACT. Growth factors affect epithelial regeneration after acute renal injury, but less is known regarding the expression of vascular growth factors in this setting. A mouse model of folic acid (FA)-induced nephrotoxicity was used to study the expression of angiopoietins (Ang), factors that bind the Tie-2 receptor and modulate endothelial growth. Tubular damage was detected 1 d after FA administration; in the next 14 d, most tubules regenerated but patchy atrophy, with interstitial fibrosis, was also observed. Ang-1 immunostaining was detected between cortical tubules and in the vasa rectae of vehicle-treated animals. FA-induced nephropathy was associated with the acquisition of Ang-1 immunostaining in renal arterial walls and in a subset of injured cortical tubules that failed to stain with periodic acid-Schiff stain, which indicated that they were distal tubules. Renal Ang-1 protein levels were significantly increased after FA administration, compared with time-matched control values, as assessed by Western blotting. Capillaries between regenerating tubules expressed both Tie-2 and platelet-endothelial cell adhesion molecule. A subset of these endothelia expressed proliferating cell nuclear antigen, whereas capillary proliferation was absent in control samples. Therefore, FA-induced nephropathy is associated with increased Ang-1 protein expression in renal epithelia and arteries. In addition, Tie-2-expressing capillaries near damaged cortical tubules undergo proliferation. Further experiments are required to establish whether these events are functionally related.

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