scholarly journals The Therapeutic Potential of Zinc-Alpha2-Glycoprotein (AZGP1) in Fibrotic Kidney Disease

2022 ◽  
Vol 23 (2) ◽  
pp. 646
Author(s):  
Inga Sörensen-Zender ◽  
Song Rong ◽  
Hermann Haller ◽  
Roland Schmitt
Keyword(s):  
Lipid Metabolism ◽  
Kidney Disease ◽  
Therapeutic Potential ◽  
Acid Oxidation ◽  
Beneficial Effects ◽  
Transgenic Mouse Strain ◽  
Proximal Tubular ◽  
Deficient Mice ◽  
Lower Expression

Chronic kidney disease (CKD) is characterized by a long-term loss of kidney function and, in most cases, by progressive fibrosis. Zinc-alpha2-glycoprotein (AZGP1) is a secreted protein, which is expressed in many different tissues and has been associated with a variety of functions. In a previous study, we have shown in cell culture and in AZGP1 deficient mice that AZGP1 has protective anti-fibrotic effects. In the present study, we tested the therapeutic potential of an experimental increase in AZGP1 using two different strategies. (1) C57Bl/6J mice were treated systemically with recombinant AZGP1, and (2) a transgenic mouse strain was generated to overexpress AZGP1 conditionally in proximal tubular cells. Mice underwent unilateral uretic obstruction as a pro-fibrotic kidney stress model, and kidneys were examined after 14 days. Recombinant AZGP1 treatment was accompanied by better preservation of tubular integrity, reduced collagen deposition, and lower expression of injury and fibrosis markers. Weaker but similar tendencies were observed in transgenic AZGP1 overexpressing mice. Higher AZGP1 levels led to a significant reduction in stress-induced accumulation of tubular lipid droplets, which was paralleled by improved expression of key players in lipid metabolism and fatty acid oxidation. Together these data show beneficial effects of elevated AZGP1 levels in fibrotic kidney disease and highlight a novel link to tubular cell lipid metabolism, which might open up new opportunities for CKD treatment.

scholarly journals Clusterin deficiency induces lipid accumulation and tissue damage in kidney

2018 ◽  
Vol 237 (2) ◽  
pp. 175-191 ◽  
Author(s):  
Jung-Yoon Heo ◽  
Ji-Eun Kim ◽  
Yongwook Dan ◽  
Yong-Woon Kim ◽  
Jong-Yeon Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Kidney Disease ◽  
Lipid Metabolism ◽  
Kidney Disease ◽  
Lipid Accumulation ◽  
Transforming Growth Factor ◽  
Lipid Levels ◽  
Lipogenic Gene ◽  
Lipogenic Gene Expression ◽  
Deficient Mice

Clusterin is a secretory glycoprotein that is involved in multiple physiopathological processes, including lipid metabolism. Previous studies have shown that clusterin prevents hepatic lipid accumulation via suppression of sterol regulatory element-binding protein (SREBP) 1. In this study, we examined the role of clusterin in renal lipid accumulation in clusterin-knockout mice and NRK52e tubular epithelial cells. Clusterin deficiency increased the expression of SREBP1 and its target genes and decreased malonyl-CoA decarboxylase protein levels in the kidney. Expression of the endocytic receptor, megalin, and scavenger receptor class A was increased in clusterin-deficient mice. Functional analysis of lipid metabolism also revealed that lipid uptake and triglyceride synthesis were increased and fatty acid oxidation was reduced, leading to increased lipid accumulation in clusterin-deficient mice. These phenomena were accompanied by mesangial expansion, fibrosis and increased urinary protein-to-creatinine ratio. High-fat feeding aggravated these clusterin deficiency-induced pathological changes. Clusterin knockdown in NRK52e cells increased lipogenic gene expression and lipid levels, whereas overexpression of clusterin by treatment with adenovirus or recombinant clusterin protein suppressed lipogenic gene expression and lipid levels. Transforming growth factor-beta 1 (TGFB1) expression increased in the kidney of clusterin-deficient mice and suppression of TGFB1 in NRK52e cells suppressed lipid accumulation. These results suggest that clusterin deficiency induces renal lipid accumulation by dysregulating the expression of lipid metabolism-related factors and TGFB1, thereby leading to chronic kidney disease. Hence, clusterin may serve as a therapeutic target for lipid-induced chronic kidney disease.

Implication of lipids in macrosomia of diabetic pregnancy: can n-3 polyunsaturated fatty acids exert beneficial effects?

2003 ◽  
Vol 105 (5) ◽  
pp. 519-529 ◽  
Author(s):  
Hafida MERZOUK ◽  
Naim A. KHAN
Keyword(s):  
Fatty Acids ◽  
Lipid Metabolism ◽  
Polyunsaturated Fatty Acids ◽  
Plasma Lipids ◽  
Diabetic Pregnancy ◽  
Infants Of Diabetic Mothers ◽  
Beneficial Effects ◽  
Obesity And Diabetes ◽  
Diabetic Mothers

Macrosomia or fetal obesity is a frequent complication of pregnancy in diabetes mellitus. Several alterations observed in carbohydrate and lipid metabolism in macrosomic infants of diabetic mothers are thought to be a consequence of maternal hyperglycaemia leading to fetal hyperinsulinaemia. Macrosomic infants of diabetic mothers are prone to the development of glucose intolerance, obesity and diabetes during childhood and adulthood. Furthermore, increasing evidence is accumulating regarding the importance of n-3 polyunsaturated fatty acids (PUFAs) in the reduction of plasma lipids and hyperglycaemia. In this review article, we shed light on the abnormalities in lipid metabolism in macrosomia. We also raise the question of the possible beneficial effects of n-3 PUFAs in diabetic pregnancy and in the prevention and treatment of long-term metabolic abnormalities associated with macrosomia.

Anabolic steroids in part reverse glucocorticoid-induced alterations in rat diaphragm

1998 ◽  
Vol 84 (5) ◽  
pp. 1492-1499 ◽  
Author(s):  
Roland H. H. Van Balkom ◽  
P. N. Richard Dekhuijzen ◽  
Hans T. M. Folgering ◽  
Jacques H. Veerkamp ◽  
Herman T. Van Moerkerk ◽  
...  
Keyword(s):  
Low Dose ◽  
Anabolic Steroids ◽  
Acid Oxidation ◽  
Type I ◽  
Adult Rats ◽  
Cross Sectional ◽  
Male Adult ◽  
Reduction In Force ◽  
Beneficial Effects

Animal and clinical studies have shown respiratory muscle dysfunction caused by treatment with glucocorticoids. The present study was designed to investigate whether anabolic steroids are able to antagonize the loss of diaphragm force induced by long-term low-dose methylprednisolone (MP) administration. Male adult rats were randomized to receive saline or MP (0.2 mg ⋅ kg−1 ⋅ day−1sc) during 9 mo, with or without nandrolone decanoate (ND; 1 mg ⋅ kg−1 ⋅ wk−1im) during the last 3 mo. The ∼10% reduction in force generation of isolated diaphragm bundles induced by MP was completely abolished by addition of ND. The MP-induced decrease in number of fibers expressing type IIb myosin heavy chains was not reversed by ND. MP slightly reduced type I, IIa, and IIx fiber cross-sectional areas (CSA), but not type IIb fiber CSA. Addition of ND abolished the reduction in IIa and IIx fiber CSA. The MP-induced alterations in glycogenolytic activity and fatty acid oxidation capacity were not reversed by ND. In conclusion, the marked reduction in diaphragm force caused by long-term low-dose MP was completely abolished by addition of ND. ND in part also antagonized the effects of MP on diaphragm morphology but showed no beneficial effects on biochemical changes.

scholarly journals Peroxisome Proliferator-Activated Receptor Targets for the Treatment of Metabolic Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-18 ◽  
Author(s):  
Francisco A. Monsalve ◽  
Radha D. Pyarasani ◽  
Fernando Delgado-Lopez ◽  
Rodrigo Moore-Carrasco
Keyword(s):  
Risk Factors ◽  
Metabolic Syndrome ◽  
Lipid Metabolism ◽  
Glucose Homeostasis ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Atherogenic Dyslipidemia ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
The Metabolic Syndrome

Metabolic syndrome is estimated to affect more than one in five adults, and its prevalence is growing in the adult and pediatric populations. The most widely recognized metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. Individuals with these characteristics commonly manifest a prothrombotic state and a proinflammatory state as well. Peroxisome proliferator-activated receptors (PPARs) may serve as potential therapeutic targets for treating the metabolic syndrome and its related risk factors. The PPARs are transcriptional factors belonging to the ligand-activated nuclear receptor superfamily. So far, three isoforms of PPARs have been identified, namely, PPAR-α, PPAR-β/δ, and PPAR-γ. Various endogenous and exogenous ligands of PPARs have been identified. PPAR-αand PPAR-γare mainly involved in regulating lipid metabolism, insulin sensitivity, and glucose homeostasis, and their agonists are used in the treatment of hyperlipidemia and T2DM. Whereas PPAR-β/δfunction is to regulate lipid metabolism, glucose homeostasis, anti-inflammation, and fatty acid oxidation and its agonists are used in the treatment of metabolic syndrome and cardiovascular diseases. This review mainly focuses on the biological role of PPARs in gene regulation and metabolic diseases, with particular focus on the therapeutic potential of PPAR modulators in the treatment of thrombosis.

scholarly journals Metabolic Derangement in Polycystic Kidney Disease Mouse Models Is Ameliorated by Mitochondrial-Targeted Antioxidants

2021 ◽  
Author(s):  
Nastaran Daneshgar ◽  
Andrew W Baguley ◽  
Peir-In Liang ◽  
Fei Wu ◽  
Yi Chu ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Mouse Models ◽  
Tca Cycle ◽  
Acid Oxidation ◽  
Polycystic Kidney ◽  
Metabolic Derangement ◽  
Beneficial Effects ◽  
Mitochondrial Ros ◽  
The Tca Cycle

ABSTRACTAutosomal dominant polycystic kidney disease (ADPKD) is characterized by progressively enlarging cysts. Here we elucidate the interplay between oxidative stress, mitochondrial dysfunction, and metabolic derangement using two mouse models of PKD1 mutation, PKD1RC/null and PKD1RC/RC. Mouse kidneys with PKD1 mutation have decreased mitochondrial complexes activity. Targeted proteomics analysis shows a significant decrease in proteins involved in the TCA cycle, fatty acid oxidation (FAO), respiratory complexes, and endogenous antioxidants. Overexpressing mitochondrial-targeted catalase (mCAT) using adeno-associated virus reduces mitochondrial ROS, oxidative damage, ameliorates the progression of PKD and partially restores expression of proteins involved in FAO and the TCA cycle. In human ADPKD cells, inducing mitochondrial ROS increased ERK1/2 phosphorylation and decreased AMPK phosphorylation, whereas the converse was observed with increased scavenging of ROS in the mitochondria. Treatment with the mitochondrial protective peptide, SS31, recapitulates the beneficial effects of mCAT, supporting its potential application as a novel therapeutic for ADPKD.

scholarly journals Environmental enrichment during the chronic phase after experimental stroke promotes functional recovery without synergistic effects of EphA4 targeted therapy

2019 ◽  
Vol 29 (4) ◽  
pp. 605-617
Author(s):  
Antina de Boer ◽  
Annet Storm ◽  
Maricel Gomez-Soler ◽  
Silke Smolders ◽  
Laura Rué ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Functional Outcome ◽  
Environmental Enrichment ◽  
Therapeutic Potential ◽  
Synergistic Effects ◽  
Chronic Phase ◽  
Axonal Guidance ◽  
Experimental Stroke ◽  
Beneficial Effects

Abstract Worldwide, stroke is the main cause of long-term adult disability. After the initial insult, most patients undergo a subacute period with intense plasticity and rapid functional improvements. This period is followed by a chronic phase where recovery reaches a plateau that is only partially modifiable by rehabilitation. After experimental stroke, various subacute rehabilitation paradigms improve recovery. However, in order to reach the best possible outcome, a combination of plasticity-promoting strategies and rehabilitation might be necessary. EphA4 is a negative axonal guidance regulator during development. After experimental stroke, reduced EphA4 levels improve functional outcome with similar beneficial effects upon the inhibition of EphA4 downstream targets. In this study, we assessed the effectiveness of a basic enriched environment in the chronic phase after photothrombotic stroke in mice as well as the therapeutic potential of EphA4 targeted therapy followed by rehabilitation. Our findings show that environmental enrichment in the chronic phase improves functional outcome up to 2 months post-stroke. Although EphA4 levels increase after experimental stroke, subacute EphA4 inhibition followed by environmental enrichment does not further increase recovery. In conclusion, we show that environmental enrichment during the chronic phase of stroke improves functional outcome in mice with no synergistic effects of the used EphA4 targeted therapy.

PARP inhibitors and the Kidney

2021 ◽  
pp. 239936932098709
Author(s):  
Priya P Deshpande ◽  
Mark A Perazella ◽  
Kenar D Jhaveri
Keyword(s):  
Kidney Disease ◽  
Gene Mutations ◽  
Kidney Injury ◽  
Parp Inhibitors ◽  
Current Data ◽  
Long Term Effects ◽  
Beneficial Effects ◽  
Anti Cancer ◽  
Proximal Tubular ◽  
End Stage

Poly (ADP-ribose) polymerases (PARPs) are crucial in repairing DNA after a damaging event. However, several studies indicate that more extensive DNA disruption causes overactivity of PARP and can ultimately lead to cellular necrosis particularly in the setting of ischemia- related or sepsis-related acute kidney injury (AKI). Though the anti-cancer effects of PARP inhibitors (PARPis) are well known, especially in cases of Breast Cancer gene mutations, there exists a potential for the use of these drugs in treating ischemic AKI. Though the beneficial effects of PARPis in attenuating ischemic AKI has been shown in animal models, testing has yet to be done in humans. Studies have also found that PARPis interact with proximal tubular transporter channels and cause a physiologic increase serum creatinine, however the long- term effects on kidney function, proteinuria and hematuria are unclear. The use of PARPis in patients with chronic kidney disease (CKD) and malignancy may result in the amplification of adverse effects such as anemia and thrombocytopenia. Safe dosing of these agents in patients with advanced CKD and end stage kidney disease (ESKD) is yet to be determined as these populations were excluded from clinical trials. This manuscript reviews the current data on the kidney effects of PARPis and opens the door to further research in this arena.

scholarly journals Cardiomyocyte-Restricted Deletion of PPARβ/δin PPARα-Null Mice Causes Impaired Mitochondrial Biogenesis and Defense, but No Further Depression of Myocardial Fatty Acid Oxidation

PPAR Research ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Jian Liu ◽  
Peiyong Wang ◽  
Lan He ◽  
Yuquan Li ◽  
Jinwen Luo ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Oxidation ◽  
Mitochondrial Biogenesis ◽  
Acid Oxidation ◽  
Key Factors ◽  
Adult Mice ◽  
Cardiac Phenotype ◽  
Pathological Development

It is well documented that PPARαand PPARβ/δshare overlapping functions in regulating myocardial lipid metabolism. However, previous studies demonstrated that cardiomyocyte-restricted PPARβ/δdeficiency in mice leads to severe cardiac pathological development, whereas global PPARαknockout shows a benign cardiac phenotype. It is unknown whether a PPARα-null background would alter the pathological development in mice with cardiomyocyte-restricted PPARβ/δdeficiency. In the present study, a mouse model with long-term PPARβ/δdeficiency in PPARα-null background showed a comparably reduced cardiac expression of lipid metabolism to those of single PPAR-deficient mouse models. The PPARα-null background did not rescue or aggravate the cardiac pathological development linked to cardiomyocyte-restricted PPARβ/δdeficiency. Moreover, PPARα-null did not alter the phenotypic development in adult mice with the short-term deletion of PPARβ/δin their hearts, which showed mitochondrial abnormalities, depressed cardiac performance, and cardiac hypertrophy with attenuated expression of key factors in mitochondrial biogenesis and defense. The present study demonstrates that cardiomyocyte-restricted deletion of PPARβ/δin PPARα-null mice causes impaired mitochondrial biogenesis and defense, but no further depression of fatty acid oxidation. Therefore, PPARβ/δis essential for maintaining mitochondrial biogenesis and defense in cardiomyocytes independent of PPARα.

scholarly journals Mesenchymal Stem Cells: The Magic Cure for Intraventricular Hemorrhage?

2017 ◽  
Vol 26 (3) ◽  
pp. 439-448 ◽  
Author(s):  
Won Soon Park ◽  
So Yoon Ahn ◽  
Se In Sung ◽  
Jee-Yin Ahn ◽  
Yun Sil Chang
Keyword(s):  
Stem Cell ◽  
Intraventricular Hemorrhage ◽  
Neonatal Intensive Care ◽  
Brain Injuries ◽  
Therapeutic Potential ◽  
Protective Action ◽  
Preclinical Study ◽  
Beneficial Effects ◽  
Study Results

Severe intraventricular hemorrhage (IVH) remains a major cause of mortality and long-term neurologic morbidities in premature infants, despite recent advances in neonatal intensive care medicine. Several preclinical studies have demonstrated the beneficial effects of mesenchymal stem cell (MSC) transplantation in attenuating brain injuries resulting from severe IVH. Because there currently exists no effective intervention for severe IVH, the therapeutic potential of MSC transplantation in this intractable and devastating disease is creating excitement in this field. This review summarizes recent progress in stem cell research for treating neonatal brain injury due to severe IVH, with a particular focus on preclinical data concerning important issues, such as mechanism of protective action and determining optimal source, route, timing, and dose of MSC transplantation, and on the translation of these preclinical study results to a clinical trial.

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