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Molecular and Cellular Mechanisms of Cardiorenal Diseases

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 25979

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Special Issue Editors

Dr. Daria Ilatovskaya

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Guest Editor

Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA
Interests: water and electrolyte homeostasis; ion channel function; cardiorenal diseases; hypertension; diabetes

Dr. Krisztian Stadler

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Guest Editor

Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, LA, USA
Interests: diabetes; insulin resistance; diabetic nephropathy(DN); redox signaling; mitochondrial metabolism

Special Issue Information

Dear Colleagues,

A Special Issue on “Molecular and Cellular Mechanisms of Cardiorenal Diseases” is being prepared for the journal Biomolecules. We are looking forward to receiving original manuscripts devoted to various aspects of cardiorenal diseases, kidney physiology and pathophysiology, and the mechanisms of cardiorenal interactions.

The epidemic of cardiorenal diseases is ever growing around the world. According to the CDC, in the United States some of the more common causes of kidney disease are diabetes and hypertension. Other risk factors include heart disease, metabolic abnormalities, and obesity. It is now clear that CKD and heart disease go hand in hand and should be considered together. Extensive research efforts are devoted to unraveling the molecular and cellular mechanisms of the cardiorenal pathologies, and new methodologies and models are being developed to reveal novel pharmacological interventions. The main goal of this Special Issue is to showcase manuscripts that have both a strong basic research background and a clear translational potential in the area of cardiac and renal physiology, injury, and disease. We encourage the submission of manuscripts that identify potential molecular and cellular mechanisms and discover new targets for cardiorenal disease, especially those focused on redox biology and/or specific inflammatory pathways as part of the mechanism. We invite manuscripts devoted (but not limited) to studies of hypertension, diabetes, chronic kidney disease, acute kidney injury, heart failure (especially in the context of CKD), and polycystic kidney disease.

Research manuscripts, translational studies, methodology papers, reports of new animal and cellular models, reviews, and mini-reviews dealing with different aspects of cardiorenal disease are welcome.

Dr. Daria Ilatovskaya
Dr. Krisztian Stadler
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

renal injury
kidney disease
hypertension
cardiorenal
heart failure
diabetic nephropathy
acute kidney injury
glomerulopathy
oxidative stress
inflammation

Published Papers (9 papers)

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Research

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19 pages, 5827 KiB

Open AccessArticle

Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular Respiration

by Surabhi Bangarbale, Blythe D. Shepard, Shivani Bansal, Meth M. Jayatilake, Ryan Kurtz, Moshe Levi and Carolyn M. Ecelbarger

Biomolecules 2022, 12(9), 1176; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12091176 - 25 Aug 2022

Cited by 4 | Viewed by 1878

Abstract

Sodium glucose cotransporter, type 2 inhibitors, such as Empagliflozin, are protective of the kidneys by unclear mechanisms. Our aim was to determine how Empagliflozin affected kidney cortical metabolome and lipidome in mice. Adult male TALLYHO mice (prone to obesity) were treated with a high-milk-fat diet, or this diet containing Empagliflozin (0.01%), for 8 weeks. Targeted and untargeted metabolomics and lipidomics were conducted on kidney cortex by liquid chromatography followed by tandem mass-spectroscopy. Metabolites were statistically analyzed by MetaboAnalyst 5.0, LipidSig (lipid species only) and/or CEU Mass Mediator (untargeted annotation). In general, volcano plotting revealed oppositely skewed patterns for targeted metabolites (primarily hydrophilic) and lipids (hydrophobic) in that polar metabolites showed a larger number of decreased species, while non-polar (lipids) had a greater number of increased species (>20% changed and/or raw p-value < 0.05). The top three pathways regulated by Empagliflozin were urea cycle, spermine/spermidine biosynthesis, and aspartate metabolism, with an amino acid network being highly affected, with 14 of 20 classic amino acids down-regulated. Out of 75 changed polar metabolites, only three were up-regulated, i.e., flavin mononucleotide (FMN), uridine, and ureidosuccinic acid. Both FMN and uridine have been shown to be protective of the kidney. Scrutiny of metabolites of glycolysis/gluconeogenesis/Krebs cycle revealed a 20–45% reduction in several species, including phosphoenolpyruvate (PEP), succinate, and malic acid. In contrast, although overall lipid quantity was not higher, several lipid species were increased by EMPA, including those of the classes, phosphatidic acids, phosphatidylcholines, and carnitines. Overall, these analyses suggest a protection from extensive metabolic load and the corresponding oxidative stress with EMPA in kidney. This may be in response to reduced energy demands of the proximal tubule as a result of inhibition of transport and/or differences in metabolic pools available for metabolism. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cardiorenal Diseases)

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16 pages, 2721 KiB

Open AccessArticle

Exosomes Derived from BM-MSCs Mitigate the Development of Chronic Kidney Damage Post-Menopause via Interfering with Fibrosis and Apoptosis

by Wardah A. Alasmari, Ahmed Abdelfattah-Hassan, Hanaa M. El-Ghazali, Samar A. Abdo, Doaa Ibrahim, Naser A. ElSawy, Eman S. El-Shetry, Ayman A. Saleh, Mohammed A. S. Abourehab and Hala Mahfouz

Biomolecules 2022, 12(5), 663; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12050663 - 02 May 2022

Cited by 14 | Viewed by 2910

Abstract

The rate of chronic kidney disease (CKD) is increasing globally, and it is caused by continuous damage to kidney tissue. With time the renal damage becomes irreversible, leading to CKD development. In females, post-menopause lack of estrogen supply has been described as a risk factor for CKD development, and studies targeting post-menopause CKD are scarce. In the present study, we used exosomes isolated from bone marrow mesenchymal stem/stromal cells (BM-MSCs) to test their therapeutic potential against the development of CKD. At first, the menopause model was achieved by surgical bilateral ovariectomy in female albino rats. After that, 100 µg of exosomes was given to ovariectomized rats, and the study continued for 2 months. Changes in urine volume, urine protein content, kidney function biochemical parameters (creatinine and BUN), kidney antioxidant parameters (SOD, GPx and CAT), histological changes, immunohistochemical levels of caspase 3, and the gene expression of NGAL (related to kidney damage), TGFβ1 and αSMA (related to fibrosis and EMT), and caspase 3 (related to apoptosis) were studied. After the ovariectomy, the occurrence of CKD was confirmed in the rats by the drastic reduction of serum estrogen and progesterone levels, reduced urine output, increased urinary protein excretion, elevated serum creatinine and BUN, reduced GPx SOD, and CAT in kidney tissue, degenerative and fibrotic lesions in the histopathological examination, higher immunohistochemical expression of caspase 3 and increased expression of all studied genes. After exosomes administration, the entire chronic inflammatory picture in the kidney was corrected, and a near-normal kidney structure and function were attained. This study shows for the first time that BM-MSCs exosomes are potent for reducing apoptosis and fibrosis levels and, thus, can reduce the chronic damage of the kidneys in females that are in their menopause period. Therefore, MSCs-derived exosomes should be considered a valuable therapy for preserving postmenopausal kidney structure and function and, subsequently, could improve the quality of females’ life during menopause. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cardiorenal Diseases)

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14 pages, 1876 KiB

Open AccessArticle

Apparent Absence of BMAL1-Dependent Skeletal Muscle–Kidney Cross Talk in Mice

by Gene Ryan Crislip, Stephanie E. Wohlgemuth, Christopher A. Wolff, Miguel A. Gutierrez-Monreal, Collin M. Douglas, Elnaz Ebrahimi, Kit-Yan Cheng, Sarah H. Masten, Dominique Barral, Andrew J. Bryant, Karyn A. Esser and Michelle L. Gumz

Biomolecules 2022, 12(2), 261; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12020261 - 05 Feb 2022

Cited by 2 | Viewed by 2483

Abstract

BMAL1 is a core mammalian circadian clock transcription factor responsible for the regulation of the expression of thousands of genes. Previously, male skeletal-muscle-specific BMAL1-inducible-knockout (iMS-BMAL1 KO) mice have been described as a model that exhibits an aging-like phenotype with an altered gait, reduced mobility, muscle weakness, and impaired glucose uptake. Given this aging phenotype and that chronic kidney disease is a disease of aging, the goal of this study was to determine if iMS-BMAL1 KO mice exhibit a renal phenotype. Male iMS-BMAL1 KO and control mice were challenged with a low potassium diet for five days. Both genotypes responded appropriately by conserving urinary potassium. The iMS-BMAL1 KO mice excreted less potassium during the rest phase during the normal diet but there was no genotype difference during the active phase. Next, iMS-BMAL1 KO and control mice were used to compare markers of kidney injury and assess renal function before and after a phase advance protocol. Following phase advance, no differences were detected in renal mitochondrial function in iMS-BMAL1 KO mice compared to control mice. Additionally, the glomerular filtration rate and renal morphology were similar between groups in response to phase advance. Disruption of the clock in skeletal muscle tissue activates inflammatory pathways within the kidney of male mice, and there is evidence of this affecting other organs, such as the lungs. However, there were no signs of renal injury or altered function following clock disruption of skeletal muscle under the conditions tested. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cardiorenal Diseases)

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20 pages, 2398 KiB

Open AccessArticle

Tempol Alters Urinary Extracellular Vesicle Lipid Content and Release While Reducing Blood Pressure during the Development of Salt-Sensitive Hypertension

by Kevin M. Chacko, Mohammad-Zaman Nouri, Whitney C. Schramm, Zeeshan Malik, Lauren P. Liu, Nancy D. Denslow and Abdel A. Alli

Biomolecules 2021, 11(12), 1804; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11121804 - 01 Dec 2021

Cited by 10 | Viewed by 2129

Abstract

Salt-sensitive hypertension resulting from an increase in blood pressure after high dietary salt intake is associated with an increase in the production of reactive oxygen species (ROS). ROS are known to increase the activity of the epithelial sodium channel (ENaC), and therefore, they have an indirect effect on sodium retention and increasing blood pressure. Extracellular vesicles (EVs) carry various molecules including proteins, microRNAs, and lipids and play a role in intercellular communication and intracellular signaling in health and disease. We investigated changes in EV lipids, urinary electrolytes, osmolality, blood pressure, and expression of renal ENaC and its adaptor protein, MARCKS/MARCKS Like Protein 1 (MLP1) after administration of the antioxidant Tempol in salt-sensitive hypertensive 129Sv mice. Our results show Tempol infusion reduces systolic blood pressure and protein expression of the alpha subunit of ENaC and MARCKS in the kidney cortex of hypertensive 129Sv mice. Our lipidomic data show an enrichment of diacylglycerols and monoacylglycerols and reduction in ceramides, dihydroceramides, and triacylglycerols in urinary EVs from these mice after Tempol treatment. These data will provide insight into our understanding of mechanisms involving strategies aimed to inhibit ROS to alleviate salt-sensitive hypertension. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cardiorenal Diseases)

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21 pages, 6678 KiB

Open AccessArticle

GYY4137 Regulates Extracellular Matrix Turnover in the Diabetic Kidney by Modulating Retinoid X Receptor Signaling

by Subir Kumar Juin, Sathnur Pushpakumar and Utpal Sen

Biomolecules 2021, 11(10), 1477; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11101477 - 07 Oct 2021

Cited by 9 | Viewed by 2326

Abstract

Diabetic kidney is associated with an accumulation of extracellular matrix (ECM) leading to renal fibrosis. Dysregulation of retinoic acid metabolism involving retinoic acid receptors (RARs) and retinoid X receptors (RXRs) has been shown to play a crucial role in diabetic nephropathy (DN). Furthermore, RARs and peroxisome proliferator-activated receptor γ (PPARγ) are known to control the RXR-mediated transcriptional regulation of several target genes involved in DN. Recently, RAR and RXR have been shown to upregulate plasminogen activator inhibitor-1 (PAI-1), a major player involved in ECM accumulation and renal fibrosis during DN. Interestingly, hydrogen sulfide (H₂S) has been shown to ameliorate adverse renal remodeling in DN. We investigated the role of RXR signaling in the ECM turnover in diabetic kidney, and whether H₂S can mitigate ECM accumulation by modulating PPAR/RAR-mediated RXR signaling. We used wild-type (C57BL/6J), diabetic (C57BL/6-Ins2^Akita/J) mice and mouse mesangial cells (MCs) as experimental models. GYY4137 was used as a H₂S donor. Results showed that in diabetic kidney, the expression of PPARγ was decreased, whereas upregulations of RXRα, RXRβ, and RARγ1 expression were observed. The changes were associated with elevated PAI-1, MMP-9 and MMP-13. In addition, the expressions of collagen IV, fibronectin and laminin were increased, whereas elastin expression was decreased in the diabetic kidney. Excessive collagen deposition was observed predominantly in the peri-glomerular and glomerular regions of the diabetic kidney. Immunohistochemical localization revealed elevated expression of fibronectin and laminin in the glomeruli of the diabetic kidney. GYY4137 reversed the pathological changes. Similar results were observed in in vitro experiments. In conclusion, our data suggest that RXR signaling plays a significant role in ECM turnover, and GYY4137 modulates PPAR/RAR-mediated RXR signaling to ameliorate PAI-1-dependent adverse ECM turnover in DN. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cardiorenal Diseases)

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Review

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13 pages, 733 KiB

Open AccessReview

Inhibiting NADPH Oxidases to Target Vascular and Other Pathologies: An Update on Recent Experimental and Clinical Studies

by Anthony L. Sylvester, David X. Zhang, Sophia Ran and Natalya S. Zinkevich

Biomolecules 2022, 12(6), 823; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12060823 - 13 Jun 2022

Cited by 13 | Viewed by 2468

Abstract

Reactive oxygen species (ROS) can be beneficial or harmful in health and disease. While low levels of ROS serve as signaling molecules to regulate vascular tone and the growth and proliferation of endothelial cells, elevated levels of ROS contribute to numerous pathologies, such as endothelial dysfunctions, colon cancer, and fibrosis. ROS and their cellular sources have been extensively studied as potential targets for clinical intervention. Whereas various ROS sources are important for different pathologies, four NADPH oxidases (NOX1, NOX2, NOX4, and NOX5) play a prominent role in homeostasis and disease. NOX1-generated ROS have been implicated in hypertension, suggesting that inhibition of NOX1 may be a promising therapeutic approach. NOX2 and NOX4 oxidases are of specific interest due to their role in producing extra- and intracellular hydrogen peroxide (H₂O₂). NOX4-released hydrogen peroxide activates NOX2, which in turn stimulates the release of mitochondrial ROS resulting in ROS-induced ROS release (RIRR) signaling. Increased ROS production from NOX5 contributes to atherosclerosis. This review aims to summarize recent findings on NOX enzymes and clinical trials inhibiting NADPH oxidases to target pathologies including diabetes, idiopathic pulmonary fibrosis (IPF), and primary biliary cholangitis (PBC). Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cardiorenal Diseases)

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13 pages, 8548 KiB

Open AccessFeature PaperReview

Nitric-Oxide-Mediated Signaling in Podocyte Pathophysiology

by Marharyta Semenikhina, Mariia Stefanenko, Denisha R. Spires, Daria V. Ilatovskaya and Oleg Palygin

Biomolecules 2022, 12(6), 745; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12060745 - 25 May 2022

Cited by 5 | Viewed by 2832

Abstract

Nitric oxide (NO) is a potent signaling molecule involved in many physiological and pathophysiological processes in the kidney. NO plays a complex role in glomerular ultrafiltration, vasodilation, and inflammation. Changes in NO bioavailability in pathophysiological conditions such as hypertension or diabetes may lead to podocyte damage, proteinuria, and rapid development of chronic kidney disease (CKD). Despite the extensive data highlighting essential functions of NO in health and pathology, related signaling in glomerular cells, particularly podocytes, is understudied. Several reports indicate that NO bioavailability in glomerular cells is decreased during the development of renal pathology, while restoring NO level can be beneficial for glomerular function. At the same time, the compromised activity of nitric oxide synthase (NOS) may provoke the formation of peroxynitrite and has been linked to autoimmune diseases such as systemic lupus erythematosus. It is known that the changes in the distribution of NO sources due to shifts in NOS subunits expression or modifications of NADPH oxidases activity may be linked to or promote the development of pathology. However, there is a lack of information about the detailed mechanisms describing the production and release of NO in the glomerular cells. The interaction of NO and other reactive oxygen species in podocytes and how NO-calcium crosstalk regulates glomerular cells’ function is still largely unknown. Here, we discuss recent reports describing signaling, synthesis, and known pathophysiological mechanisms mediated by the changes in NO homeostasis in the podocyte. The understanding and further investigation of these essential mechanisms in glomerular cells will facilitate the design of novel strategies to prevent or manage health conditions that cause glomerular and kidney damage. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cardiorenal Diseases)

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24 pages, 1627 KiB

Open AccessFeature PaperReview

Emerging Roles for G Protein-Coupled Estrogen Receptor 1 in Cardio-Renal Health: Implications for Aging

by Ravneet Singh, Victoria L. Nasci, Ginger Guthrie, Lale A. Ertuglu, Maryam K. Butt, Annet Kirabo and Eman Y. Gohar

Biomolecules 2022, 12(3), 412; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12030412 - 07 Mar 2022

Cited by 4 | Viewed by 4325

Abstract

Cardiovascular (CV) and renal diseases are increasingly prevalent in the United States and globally. CV-related mortality is the leading cause of death in the United States, while renal-related mortality is the 8th. Despite advanced therapeutics, both diseases persist, warranting continued exploration of disease mechanisms to develop novel therapeutics and advance clinical outcomes for cardio-renal health. CV and renal diseases increase with age, and there are sex differences evident in both the prevalence and progression of CV and renal disease. These age and sex differences seen in cardio-renal health implicate sex hormones as potentially important regulators to be studied. One such regulator is G protein-coupled estrogen receptor 1 (GPER1). GPER1 has been implicated in estrogen signaling and is expressed in a variety of tissues including the heart, vasculature, and kidney. GPER1 has been shown to be protective against CV and renal diseases in different experimental animal models. GPER1 actions involve multiple signaling pathways: interaction with aldosterone and endothelin-1 signaling, stimulation of the release of nitric oxide, and reduction in oxidative stress, inflammation, and immune infiltration. This review will discuss the current literature regarding GPER1 and cardio-renal health, particularly in the context of aging. Improving our understanding of GPER1-evoked mechanisms may reveal novel therapeutics aimed at improving cardio-renal health and clinical outcomes in the elderly. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cardiorenal Diseases)

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Graphical abstract

20 pages, 869 KiB

Open AccessReview

Organized Chaos: Deciphering Immune Cell Heterogeneity’s Role in Inflammation in the Heart

by Alexa Corker, Lily S. Neff, Philip Broughton, Amy D. Bradshaw and Kristine Y. DeLeon-Pennell

Biomolecules 2022, 12(1), 11; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12010011 - 22 Dec 2021

Cited by 12 | Viewed by 3258

Abstract

During homeostasis, immune cells perform daily housekeeping functions to maintain heart health by acting as sentinels for tissue damage and foreign particles. Resident immune cells compose 5% of the cellular population in healthy human ventricular tissue. In response to injury, there is an increase in inflammation within the heart due to the influx of immune cells. Some of the most common immune cells recruited to the heart are macrophages, dendritic cells, neutrophils, and T-cells. In this review, we will discuss what is known about cardiac immune cell heterogeneity during homeostasis, how these cell populations change in response to a pathology such as myocardial infarction or pressure overload, and what stimuli are regulating these processes. In addition, we will summarize technologies used to evaluate cell heterogeneity in models of cardiovascular disease. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cardiorenal Diseases)

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