Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
8.1
4.9
Journals
IJMS
Special Issues
Recent Advances in Molecular Mechanisms of Kidney Injury and Repair
ijms-logo
Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

► Journal Menu

Journal Browser

► Journal Browser
share announcement

Recent Advances in Molecular Mechanisms of Kidney Injury and Repair

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 67526

Special Issue Editor

Prof. Dr. Grazyna Nowak

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AK, USA
Interests: ischemia- and toxicant-induced acute kidney injury; bioenergetics; mitochondrial dysfunction; protein phosphorylation; proteomics; protein kinases; cell injury; mechanisms of cell death
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Kidney disease remains a global public health concern because of high morbidity and mortality, and significant healthcare costs are associated with this disease. Diabetes and hypertension are the major causes of chronic kidney disease, which gradually leads to reduced quality of life and well-being. Ischemia, hypoxia, exposure to nephrotoxic compounds, and infections are the leading causes of acute kidney injury, which is encountered in a variety of clinical settings and is characterized by a rapid decline in kidney function and the failure to regulate fluid, electrolyte, and acid–base balance. The kidney has a remarkable ability to repair and regenerate its morphology and functions. However, inflammatory response and incomplete or maladaptive repair of the kidney after acute injury can lead to fibrosis and chronic kidney disease. Thus, acute kidney injury is a major risk factor for chronic and end-stage renal diseases. The therapeutic strategies used to treat acute kidney injury are still insufficient and dialysis remains the major therapeutic intervention to improve kidney recovery and patient survival.

Acute injury and chronic disease of the kidney in humans are multifactorial events. The pathogenesis of acute kidney injury is associated with a series of cellular responses to the initial insult that involve different cellular compartments, pathways and mechanisms, and a large variety of molecular targets. These responses involve protein unfolding and loss of function, DNA damage, cell cycle and growth arrest, mitochondrial dysfunction and changes in the energy metabolism, endoplasmic reticulum and oxidative stress, alterations in gene transcription and translation, disruption of biosignaling pathways, innate immune response, increased autophagy, and cell death. If the injury and stress are not too severe, repair processes are activated to replace lost cells, restore cellular metabolism and functions, and recover kidney functions. If the insult is prolonged or too severe, cellular stress and tissue dysfunction continue and the inflammatory cells are recruited to the kidney, initiating a sequelae of events leading to inflammation, fibrosis, and eventually the progressive loss of function characteristic of chronic kidney disease. Progress made in understanding these complex pathophysiological mechanisms and cellular events resulted in the development of several new biomarkers to diagnose acute kidney injury and its progression to chronic kidney disease. Hopefully, the continuation of studies into these areas will lead to the development of therapeutic approaches that prevent and/or treat acute kidney injury, or block the progression to chronic and end-stage renal diseases.

This Special Issue of IJMS seeks manuscripts that 1) identify subcellular and molecular targets that are involved in mediating renal cell injury, preventing injury of renal cells, and/or promoting repair of these cells after injury, 2) elucidate cellular, subcellular, and molecular mechanisms and pathways mediating kidney injury, repair, and recovery, 3) describe new animal models that better represent these mechanisms in human kidneys, and 4) propose therapeutic interventions to diminish or treat kidney injury or promote kidney recovery. We encourage scientists working in this area of research to submit original research articles, communications, or critical reviews that synthesize the current literature and discuss emerging directions. Thus, these studies will contribute to the development of therapeutic interventions that target the mechanisms of kidney injury and repair.

Prof. Dr. Grazyna Nowak
Guest Editor

Keywords

  • Pathogenesis of acute and chronic kidney injury
  • Ischemic and nephrotoxic kidney injury
  • Glomerular/interstitial/vascular damage
  • Tubular necrosis, necroptosis, apoptosis, pyroptosis, and ferroptosis
  • Inflammatory signals and fibrosis
  • Bioenergetics, mitochondrial damage and biogenesis
  • Autophagy and mitophagy
  • Transcription factors in kidney injury
  • Receptors and signaling pathways
  • Cell cycle proteins
  • Biomarkers
  • Renal repair and regeneration
  • Cytoprotection and therapeutic intervention
  • In vivo and in vitro models of kidney injury

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (18 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

13 pages, 6102 KiB  
Article
Unexpected Enhancement of Cytotoxicity of Cisplatin in a Rat Kidney Proximal Tubular Cell Line Overexpressing Mitochondrial Glutathione Transport Activity
by Lawrence H. Lash
Int. J. Mol. Sci. 2022, 23(4), 1993; https://doi.org/10.3390/ijms23041993 - 11 Feb 2022
Cited by 2 | Viewed by 2014
Abstract
In previous studies, we identified the two principal transporters that mediate the uptake of glutathione (GSH) from cytoplasm into the mitochondrial matrix of rat kidney proximal tubular cells. We hypothesized that genetic modulation of transporter expression could markedly alter susceptibility of renal proximal [...] Read more.
In previous studies, we identified the two principal transporters that mediate the uptake of glutathione (GSH) from cytoplasm into the mitochondrial matrix of rat kidney proximal tubular cells. We hypothesized that genetic modulation of transporter expression could markedly alter susceptibility of renal proximal tubular cells to a broad array of oxidants and mitochondrial toxicants. Indeed, we previously showed that overexpression of either of these transporters resulted in diminished susceptibility to several chemicals. In the present work, we investigated the influence of overexpression of the mitochondrial 2-oxoglutarate carrier (OGC) in NRK-52E cells on the cytotoxicity of the antineoplastic drug cisplatin. In contrast to previous results showing that overexpression of the mitochondrial OGC provided substantial protection of NRK-52E cells from injury due to several toxicants, we found a remarkable enhancement of cellular injury from exposure to cisplatin as compared to wild-type NRK-52E cells. Despite the oxidative stress that cisplatin is known to cause in the renal proximal tubule, the increased concentrations of mitochondrial GSH associated with OGC overexpression likely resulted in increased delivery of cisplatin to molecular targets and increased cellular injury rather than the typical protection observed in the previous work. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

18 pages, 1956 KiB  
Article
Identifying Candidate Protein Markers of Acute Kidney Injury in Acute Decompensated Heart Failure
by Evelyn M. Templeton, Moritz Lassé, Torsten Kleffmann, Leigh J. Ellmers, Suetonia C. Palmer, Trent Davidson, Nicola J. A. Scott, John W. Pickering, Christopher J. Charles, Zoltan H. Endre, Vicky A. Cameron, A. Mark Richards, Miriam T. Rademaker and Anna P. Pilbrow
Int. J. Mol. Sci. 2022, 23(2), 1009; https://doi.org/10.3390/ijms23021009 - 17 Jan 2022
Viewed by 3022
Abstract
One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)—an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to [...] Read more.
One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)—an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to date, no protein biomarkers have exhibited sufficient diagnostic or prognostic performance for widespread clinical uptake. We aimed to identify novel protein biomarkers of AKI associated with ADHF by quantifying changes in protein abundance in the kidneys that occur during ADHF development and recovery in an ovine model. Relative quantitative protein profiling was performed using sequential window acquisition of all theoretical fragment ion spectra–mass spectrometry (SWATH–MS) in kidney cortices from control sheep (n = 5), sheep with established rapid-pacing-induced ADHF (n = 8), and sheep after ~4 weeks recovery from ADHF (n = 7). Of the 790 proteins quantified, we identified 17 candidate kidney injury markers in ADHF, 1 potential kidney marker of ADHF recovery, and 2 potential markers of long-term renal impairment (differential abundance between groups of 1.2–2.6-fold, adjusted p < 0.05). Among these 20 candidate protein markers of kidney injury were 6 candidates supported by existing evidence and 14 novel candidates not previously implicated in AKI. Proteins of differential abundance were enriched in pro-inflammatory signalling pathways: glycoprotein VI (activated during ADHF development; adjusted p < 0.01) and acute phase response (repressed during recovery from ADHF; adjusted p < 0.01). New biomarkers for the early detection of AKI in ADHF may help us to evaluate effective treatment strategies to prevent mortality and improve outcomes for patients. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Graphical abstract

17 pages, 4586 KiB  
Article
Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease
by Sonja Djudjaj, Panagiotis Kavvadas, Niki Prakoura, Roman D. Bülow, Tiffany Migeon, Sandrine Placier, Christos E. Chadjichristos, Peter Boor and Christos Chatziantoniou
Int. J. Mol. Sci. 2022, 23(2), 884; https://doi.org/10.3390/ijms23020884 - 14 Jan 2022
Cited by 3 | Viewed by 2866
Abstract
Background: Polycystic kidney disease (PKD) is a genetic disorder affecting millions of people worldwide that is characterized by fluid-filled cysts and leads to end-stage renal disease (ESRD). The hallmarks of PKD are proliferation and dedifferentiation of tubular epithelial cells, cellular processes known to [...] Read more.
Background: Polycystic kidney disease (PKD) is a genetic disorder affecting millions of people worldwide that is characterized by fluid-filled cysts and leads to end-stage renal disease (ESRD). The hallmarks of PKD are proliferation and dedifferentiation of tubular epithelial cells, cellular processes known to be regulated by Notch signaling. Methods: We found increased Notch3 expression in human PKD and renal cell carcinoma biopsies. To obtain insight into the underlying mechanisms and the functional consequences of this abnormal expression, we developed a transgenic mouse model with conditional overexpression of the intracellular Notch3 (ICN3) domain specifically in renal tubules. We evaluated the alterations in renal function (creatininemia, BUN) and structure (cysts, fibrosis, inflammation) and measured the expression of several genes involved in Notch signaling and the mechanisms of inflammation, proliferation, dedifferentiation, fibrosis, injury, apoptosis and regeneration. Results: After one month of ICN3 overexpression, kidneys were larger with tubules grossly enlarged in diameter, with cell hypertrophy and hyperplasia, exclusively in the outer stripe of the outer medulla. After three months, mice developed numerous cysts in proximal and distal tubules. The cysts had variable sizes and were lined with a single- or multilayered, flattened, cuboid or columnar epithelium. This resulted in epithelial hyperplasia, which was observed as protrusions into the cystic lumen in some of the renal cysts. The pre-cystic and cystic epithelium showed increased expression of cytoskeletal filaments and markers of epithelial injury and dedifferentiation. Additionally, the epithelium showed increased proliferation with an aberrant orientation of the mitotic spindle. These phenotypic tubular alterations led to progressive interstitial inflammation and fibrosis. Conclusions: In summary, Notch3 signaling promoted tubular cell proliferation, the alignment of cell division, dedifferentiation and hyperplasia, leading to cystic kidney diseases and pre-neoplastic lesions. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

13 pages, 2386 KiB  
Article
Protective Effect of Gamma Aminobutyric Acid against Aggravation of Renal Injury Caused by High Salt Intake in Cisplatin-Induced Nephrotoxicity
by Hyesook Lee, Seon Yeong Ji, Hyun Hwangbo, Min Yeong Kim, Da Hye Kim, Beom Su Park, Joung-Hyun Park, Bae-Jin Lee, Gi-Young Kim, You-Jin Jeon and Yung Hyun Choi
Int. J. Mol. Sci. 2022, 23(1), 502; https://doi.org/10.3390/ijms23010502 - 3 Jan 2022
Cited by 8 | Viewed by 3246
Abstract
Gamma-aminobutyric acid (GABA) is one of the inhibitory neurotransmitters. Several studies have suggested that GABA supplements can reduce blood pressure and modulate the renal immune system in vitro and in vivo. In the present study, we investigated the effect of GABA-enriched salt as [...] Read more.
Gamma-aminobutyric acid (GABA) is one of the inhibitory neurotransmitters. Several studies have suggested that GABA supplements can reduce blood pressure and modulate the renal immune system in vitro and in vivo. In the present study, we investigated the effect of GABA-enriched salt as an alternative to traditional salt on aggravated renal injury by high salt intake in cisplatin-induced nephrotoxicity mice. High salt intake accelerated the increase of biomarkers, such as blood urea nitrogen and serum creatinine levels for renal injury in cisplatin-induced nephrotoxicity mice. However, oral administration of GABA-contained salt notably suppressed serum BUN and creatinine levels. The efficacy of GABA salt was superior to lacto GABA salt and postbiotics GABA salt. Furthermore, GABA-enriched salt markedly restored histological symptoms of nephrotoxicity including renal hypertrophy, tubular dilation, hemorrhage, and collagen deposition aggravated by salt over-loading in cisplatin-exposed mice. Among them, GABA salt showed a higher protective effect against cisplatin-induced renal histological changes than lacto GABA salt and postbiotics GABA salt. In addition, administration of high salt significantly enhanced expression levels of apoptosis and inflammatory mediators in cisplatin-induced nephrotoxicity mice, while GABA-enriched salt greatly down-regulated the expression of these mediators. Taken together, these results demonstrate the protective effect of GABA against damage caused by high salt intake in cisplatin-induced renal toxicity. Its mechanism may be due to the suppression of hematological and biochemical toxicity, apoptosis, and inflammation. In conclusion, although the protective efficacy of GABA salt on renal injury is different depending on the sterilization and filtration process after fermentation with L. brevis BJ20 and L. plantarum BJ21, our findings suggest that GABA-enriched salt has a beneficial effect against immoderate high salt intake-mediated kidney injury in patients with cisplatin-induced nephrotoxicity. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

14 pages, 5112 KiB  
Article
A Novel Renoprotective Strategy: Upregulation of PD-L1 Mitigates Cisplatin-Induced Acute Kidney Injury
by Jun Liu, David C. Yang, Jun Zhang, Ssu-Wei Hsu, Robert H. Weiss and Ching-Hsien Chen
Int. J. Mol. Sci. 2021, 22(24), 13304; https://doi.org/10.3390/ijms222413304 - 10 Dec 2021
Cited by 5 | Viewed by 3111
Abstract
The innate and adaptive immunities have been documented to participate in the pathogenesis of nephrotoxic acute kidney injury (AKI); however, the mechanisms controlling these processes have yet to be established. In our cisplatin-induced AKI mouse model, we show pathological damage to the kidneys, [...] Read more.
The innate and adaptive immunities have been documented to participate in the pathogenesis of nephrotoxic acute kidney injury (AKI); however, the mechanisms controlling these processes have yet to be established. In our cisplatin-induced AKI mouse model, we show pathological damage to the kidneys, with the classical markers elevated, consistent with the response to cisplatin treatment. Through assessments of the components of the immune system, both locally and globally, we demonstrate that the immune microenvironment of injured kidneys was associated with an increased infiltration of CD4+ T cells and macrophages concomitant with decreased Treg cell populations. Our cell-based assays and animal studies further show that cisplatin exposure downregulated the protein levels of programmed death-ligand 1 (PD-L1), an immune checkpoint protein, in primary renal proximal tubular epithelial cells, and that these inhibitions were dose-dependent. After orthotopic delivery of PD-L1 gene into the kidneys, cisplatin-exposed mice displayed lower levels of both serum urea nitrogen and creatinine upon PD-L1 expression. Our data suggest a renoprotective effect of the immune checkpoint protein, and thereby provide a novel therapeutic strategy for cisplatin-induced AKI. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

23 pages, 5327 KiB  
Article
γ-Tocotrienol Protects against Mitochondrial Dysfunction, Energy Deficits, Morphological Damage, and Decreases in Renal Functions after Renal Ischemia
by Grazyna Nowak and Judit Megyesi
Int. J. Mol. Sci. 2021, 22(23), 12674; https://doi.org/10.3390/ijms222312674 - 24 Nov 2021
Cited by 4 | Viewed by 1962
Abstract
Ischemia-induced mitochondrial dysfunction and ATP depletion in the kidney result in disruption of primary functions and acute injury of the kidney. This study tested whether γ-tocotrienol (GTT), a member of the vitamin E family, protects mitochondrial function, reduces ATP deficits, and improves renal [...] Read more.
Ischemia-induced mitochondrial dysfunction and ATP depletion in the kidney result in disruption of primary functions and acute injury of the kidney. This study tested whether γ-tocotrienol (GTT), a member of the vitamin E family, protects mitochondrial function, reduces ATP deficits, and improves renal functions and survival after ischemia/reperfusion injury. Vehicle or GTT (200 mg/kg) were administered to mice 12 h before bilateral kidney ischemia, and endpoints were assessed at different timepoints of reperfusion. GTT treatment reduced decreases in state 3 respiration and accelerated recovery of this function after ischemia. GTT prevented decreases in activities of complexes I and III of the respiratory chain, and blocked ischemia-induced decreases in F0F1-ATPase activity and ATP content in renal cortical tissue. GTT improved renal morphology at 72 h after ischemia, reduced numbers of necrotic proximal tubular and inflammatory cells, and enhanced tubular regeneration. GTT treatment ameliorated increases in plasma creatinine levels and accelerated recovery of creatinine levels after ischemia. Lastly, 89% of mice receiving GTT and 70% of those receiving vehicle survived ischemia. Conclusions: Our data show novel observations that GTT administration improves mitochondrial respiration, prevents ATP deficits, promotes tubular regeneration, ameliorates decreases in renal functions, and increases survival after acute kidney injury in mice. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

17 pages, 4169 KiB  
Article
Repurposing Riociguat to Target a Novel Paracrine Nitric Oxide-TRPC6 Pathway to Prevent Podocyte Injury
by Daan ‘t Hart, Jinhua Li, Johan van der Vlag and Tom Nijenhuis
Int. J. Mol. Sci. 2021, 22(22), 12485; https://doi.org/10.3390/ijms222212485 - 19 Nov 2021
Cited by 6 | Viewed by 2959
Abstract
Increased expression and activity of the Ca2+ channel transient receptor potential channel 6 (TRPC6) is associated with focal segmental glomerulosclerosis, but therapeutic strategies to target TRPC6 are currently lacking. Nitric oxide (NO) is crucial for normal glomerular function and plays a protective [...] Read more.
Increased expression and activity of the Ca2+ channel transient receptor potential channel 6 (TRPC6) is associated with focal segmental glomerulosclerosis, but therapeutic strategies to target TRPC6 are currently lacking. Nitric oxide (NO) is crucial for normal glomerular function and plays a protective role in preventing glomerular diseases. We investigated if NO prevents podocyte injury by inhibiting injurious TRPC6-mediated signaling in a soluble guanylate cyclase (sGC)-dependent manner and studied the therapeutic potential of the sGC stimulator Riociguat. Experiments were performed using human glomerular endothelial cells and podocytes. Podocyte injury was induced by Adriamycin incubation for 24 h, with or without the NO-donor S-Nitroso-N-acetyl-DL-penicillamine (SNAP), the sGC stimulator Riociguat or the TRPC6 inhibitor Larixyl Acetate (LA). NO and Riociguat stimulated cGMP synthesis in podocytes, decreased Adriamycin-induced TRPC6 expression, inhibited the Adriamycin-induced TRPC6-mediated Ca2+ influx and reduced podocyte injury. The protective effects of Riociguat and NO were blocked when sGC activity was inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or when TRPC6 activity was inhibited by LA. Our data demonstrate a glomerular (e)NOS-NO-sGC-cGMP-TRPC6 pathway that prevents podocyte injury, which can be translated to future clinical use by, e.g., repurposing the market-approved drug Riociguat. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

13 pages, 7340 KiB  
Article
CD73 Overexpression in Podocytes: A Novel Marker of Podocyte Injury in Human Kidney Disease
by Zoran V. Popovic, Felix Bestvater, Damir Krunic, Bernhard K. Krämer, Raoul Bergner, Christian Löffler, Berthold Hocher, Alexander Marx and Stefan Porubsky
Int. J. Mol. Sci. 2021, 22(14), 7642; https://doi.org/10.3390/ijms22147642 - 16 Jul 2021
Cited by 2 | Viewed by 2976
Abstract
The CD73 pathway is an important anti-inflammatory mechanism in various disease settings. Observations in mouse models suggested that CD73 might have a protective role in kidney damage; however, no direct evidence of its role in human kidney disease has been described to date. [...] Read more.
The CD73 pathway is an important anti-inflammatory mechanism in various disease settings. Observations in mouse models suggested that CD73 might have a protective role in kidney damage; however, no direct evidence of its role in human kidney disease has been described to date. Here, we hypothesized that podocyte injury in human kidney diseases alters CD73 expression that may facilitate the diagnosis of podocytopathies. We assessed the expression of CD73 and one of its functionally important targets, the C-C chemokine receptor type 2 (CCR2), in podocytes from kidney biopsies of 39 patients with podocytopathy (including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous glomerulonephritis (MGN) and amyloidosis) and a control group. Podocyte CD73 expression in each of the disease groups was significantly increased in comparison to controls (p < 0.001–p < 0.0001). Moreover, there was a marked negative correlation between CD73 and CCR2 expression, as confirmed by immunohistochemistry and immunofluorescence (Pearson r = −0.5068, p = 0.0031; Pearson r = −0.4705, p = 0.0313, respectively), thus suggesting a protective role of CD73 in kidney injury. Finally, we identify CD73 as a novel potential diagnostic marker of human podocytopathies, particularly of MCD that has been notorious for the lack of pathological features recognizable by light microscopy and immunohistochemistry. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

19 pages, 5336 KiB  
Article
Methylglyoxal-Derived Advanced Glycation End Product (AGE4)-Induced Apoptosis Leads to Mitochondrial Dysfunction and Endoplasmic Reticulum Stress through the RAGE/JNK Pathway in Kidney Cells
by So-Ra Jeong and Kwang-Won Lee
Int. J. Mol. Sci. 2021, 22(12), 6530; https://doi.org/10.3390/ijms22126530 - 18 Jun 2021
Cited by 20 | Viewed by 3526
Abstract
Advanced glycation end products (AGEs) are formed via nonenzymatic reactions between reducing sugars and proteins. Recent studies have shown that methylglyoxal, a potent precursor for AGEs, causes a variety of biological dysfunctions, including diabetes, inflammation, renal failure, and cancer. However, little is known [...] Read more.
Advanced glycation end products (AGEs) are formed via nonenzymatic reactions between reducing sugars and proteins. Recent studies have shown that methylglyoxal, a potent precursor for AGEs, causes a variety of biological dysfunctions, including diabetes, inflammation, renal failure, and cancer. However, little is known about the function of methylglyoxal-derived AGEs (AGE4) in kidney cells. Therefore, we verified the expression of endoplasmic reticulum (ER) stress-related genes and apoptosis markers to determine the effects of AGE4 on human proximal epithelial cells (HK-2). Moreover, our results showed that AGE4 induced the expression of apoptosis markers, such as Bax, p53, and kidney injury molecule-1, but downregulated Bcl-2 and cyclin D1 levels. AGE4 also promoted the expression of NF-κB, serving as a transcription factor, and the phosphorylation of c-Jun NH2-terminal kinase (JNK), which induced cell apoptosis and ER stress mediated by the JNK inhibitor. Furthermore, AGE4 induced mitochondrial dysfunction by inducing the permeabilization of the mitochondrial membrane and ATP synthesis. Through in vitro and in vivo experiments, this study provides a new perspective on renal dysfunction with regard to the AGE4-induced RAGE /JNK signaling pathway, which leads to renal cell apoptosis via the imbalance of mitochondrial function and ER stress in kidney damage. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

Review

Jump to: Research

16 pages, 1809 KiB  
Review
Galectin-3 in Kidney Diseases: From an Old Protein to a New Therapeutic Target
by Louis Boutin, François Dépret, Etienne Gayat, Matthieu Legrand and Christos E. Chadjichristos
Int. J. Mol. Sci. 2022, 23(6), 3124; https://doi.org/10.3390/ijms23063124 - 14 Mar 2022
Cited by 17 | Viewed by 4809
Abstract
Galectin-3 (Gal-3) is a 30KDa lectin implicated in multiple pathophysiology pathways including renal damage and fibrosis. Gal-3 binds β-galactoside through its carbohydrate-recognition domain. From intra-cellular to extra-cellular localization, Gal-3 has multiple roles including transduction signal pathway, cell-to-cell adhesion, cell to extracellular matrix adhesion, [...] Read more.
Galectin-3 (Gal-3) is a 30KDa lectin implicated in multiple pathophysiology pathways including renal damage and fibrosis. Gal-3 binds β-galactoside through its carbohydrate-recognition domain. From intra-cellular to extra-cellular localization, Gal-3 has multiple roles including transduction signal pathway, cell-to-cell adhesion, cell to extracellular matrix adhesion, and immunological chemoattractant protein. Moreover, Gal-3 has also been linked to kidney disease in both preclinical models and clinical studies. Gal-3 inhibition appears to improve renal disease in several pathological conditions, thus justifying the development of multiple drug inhibitors. This review aims to summarize the latest literature regarding Gal-3 in renal pathophysiology, from its role as a biomarker to its potential as a therapeutic agent. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

16 pages, 10197 KiB  
Review
Disruption of Kidney–Immune System Crosstalk in Sepsis with Acute Kidney Injury: Lessons Learned from Animal Models and Their Application to Human Health
by Kaice LaFavers
Int. J. Mol. Sci. 2022, 23(3), 1702; https://doi.org/10.3390/ijms23031702 - 1 Feb 2022
Cited by 16 | Viewed by 3209
Abstract
In addition to being a leading cause of morbidity and mortality worldwide, sepsis is also the most common cause of acute kidney injury (AKI). When sepsis leads to the development of AKI, mortality increases dramatically. Since the cardinal feature of sepsis is a [...] Read more.
In addition to being a leading cause of morbidity and mortality worldwide, sepsis is also the most common cause of acute kidney injury (AKI). When sepsis leads to the development of AKI, mortality increases dramatically. Since the cardinal feature of sepsis is a dysregulated host response to infection, a disruption of kidney–immune crosstalk is likely to be contributing to worsening prognosis in sepsis with acute kidney injury. Since immune-mediated injury to the kidney could disrupt its protein manufacturing capacity, an investigation of molecules mediating this crosstalk not only helps us understand the sepsis immune response, but also suggests that their supplementation could have a therapeutic effect. Erythropoietin, vitamin D and uromodulin are known to mediate kidney–immune crosstalk and their disrupted production could impact morbidity and mortality in sepsis with acute kidney injury. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

19 pages, 588 KiB  
Review
Endothelial Dysfunction: An Intermediate Clinical Feature between Urolithiasis and Cardiovascular Diseases
by Javier Saenz-Medina, Mercedes Muñoz, Claudia Rodriguez, Ana Sanchez, Cristina Contreras, Joaquín Carballido-Rodríguez and Dolores Prieto
Int. J. Mol. Sci. 2022, 23(2), 912; https://doi.org/10.3390/ijms23020912 - 14 Jan 2022
Cited by 16 | Viewed by 4314
Abstract
An epidemiological relationship between urolithiasis and cardiovascular diseases has extensively been reported. Endothelial dysfunction is an early pathogenic event in cardiovascular diseases and has been associated with oxidative stress and low chronic inflammation in hypertension, coronary heart disease, stroke or the vascular complications [...] Read more.
An epidemiological relationship between urolithiasis and cardiovascular diseases has extensively been reported. Endothelial dysfunction is an early pathogenic event in cardiovascular diseases and has been associated with oxidative stress and low chronic inflammation in hypertension, coronary heart disease, stroke or the vascular complications of diabetes and obesity. The aim of this study is to summarize the current knowledge about the pathogenic mechanisms of urolithiasis in relation to the development of endothelial dysfunction and cardiovascular morbidities. Methods: A non-systematic review has been performed mixing the terms “urolithiasis”, “kidney stone” or “nephrolithiasis” with “cardiovascular disease”, “myocardial infarction”, “stroke”, or “endothelial dysfunction”. Results: Patients with nephrolithiasis develop a higher incidence of cardiovascular disease with a relative risk estimated between 1.20 and 1.24 and also develop a higher vascular disease risk scores. Analyses of subgroups have rendered inconclusive results regarding gender or age. Endothelial dysfunction has also been strongly associated with urolithiasis in clinical studies, although no systemic serum markers of endothelial dysfunction, inflammation or oxidative stress could be clearly related. Analysis of urine composition of lithiasic patients also detected a higher expression of proteins related to cardiovascular disease. Experimental models of hyperoxaluria have also found elevation of serum endothelial dysfunction markers. Conclusions: Endothelial dysfunction has been strongly associated with urolithiasis and based on the experimental evidence, should be considered as an intermediate and changeable feature between urolithiasis and cardiovascular diseases. Oxidative stress, a key pathogenic factor in the development of endothelial dysfunction has been also pointed out as an important factor of lithogenesis. Special attention must be paid to cardiovascular morbidities associated with urolithiasis in order to take advantage of pleiotropic effects of statins, angiotensin receptor blockers and allopurinol. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

19 pages, 3790 KiB  
Review
Carbamylated Proteins in Renal Disease: Aggravating Factors or Just Biomarkers?
by Laëtitia Gorisse, Stéphane Jaisson, Christine Piétrement and Philippe Gillery
Int. J. Mol. Sci. 2022, 23(1), 574; https://doi.org/10.3390/ijms23010574 - 5 Jan 2022
Cited by 7 | Viewed by 4561
Abstract
Carbamylation is a nonenzymatic post-translational modification resulting from the reaction between cyanate, a urea by-product, and proteins. In vivo and in vitro studies have demonstrated that carbamylation modifies protein structures and functions, triggering unfavourable molecular and cellular responses. An enhanced formation of carbamylation-derived [...] Read more.
Carbamylation is a nonenzymatic post-translational modification resulting from the reaction between cyanate, a urea by-product, and proteins. In vivo and in vitro studies have demonstrated that carbamylation modifies protein structures and functions, triggering unfavourable molecular and cellular responses. An enhanced formation of carbamylation-derived products (CDPs) is observed in pathological contexts, especially during chronic kidney disease (CKD), because of increased blood urea. Significantly, studies have reported a positive correlation between serum CDPs and the evolutive state of renal failure. Further, serum concentrations of carbamylated proteins are characterized as strong predictors of mortality in end-stage renal disease patients. Over time, it is likely that these modified compounds become aggravating factors and promote long-term complications, including cardiovascular disorders and inflammation or immune system dysfunctions. These poor clinical outcomes have led researchers to consider strategies to prevent or slow down CDP formation. Even if growing evidence suggests the involvement of carbamylation in the pathophysiology of CKD, the real relevance of carbamylation is still unclear: is it a causal phenomenon, a metabolic consequence or just a biological feature? In this review, we discuss how carbamylation, a consequence of renal function decline, may become a causal phenomenon of kidney disease progression and how CDPs may be used as biomarkers. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

17 pages, 360 KiB  
Review
Human Glucose Transporters in Renal Glucose Homeostasis
by Aleksandra Sędzikowska and Leszek Szablewski
Int. J. Mol. Sci. 2021, 22(24), 13522; https://doi.org/10.3390/ijms222413522 - 16 Dec 2021
Cited by 19 | Viewed by 6203
Abstract
The kidney plays an important role in glucose homeostasis by releasing glucose into the blood stream to prevent hypoglycemia. It is also responsible for the filtration and subsequent reabsorption or excretion of glucose. As glucose is hydrophilic and soluble in water, it is [...] Read more.
The kidney plays an important role in glucose homeostasis by releasing glucose into the blood stream to prevent hypoglycemia. It is also responsible for the filtration and subsequent reabsorption or excretion of glucose. As glucose is hydrophilic and soluble in water, it is unable to pass through the lipid bilayer on its own; therefore, transport takes place using carrier proteins localized to the plasma membrane. Both sodium-independent glucose transporters (GLUT proteins) and sodium-dependent glucose transporters (SGLT proteins) are expressed in kidney tissue, and mutations of the genes coding for these glucose transporters lead to renal disorders and diseases, including renal cancers. In addition, several diseases may disturb the expression and/or function of renal glucose transporters. The aim of this review is to describe the role of the kidney in glucose homeostasis and the contribution of glucose transporters in renal physiology and renal diseases. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
18 pages, 1643 KiB  
Review
Role of Endothelial Glucocorticoid Receptor in the Pathogenesis of Kidney Diseases
by Jarosław Przybyciński, Sylwester Drożdżal, Leszek Domański, Violetta Dziedziejko and Andrzej Pawlik
Int. J. Mol. Sci. 2021, 22(24), 13295; https://doi.org/10.3390/ijms222413295 - 10 Dec 2021
Cited by 6 | Viewed by 3653
Abstract
Glucocorticoids, as multifunctional hormones, are widely used in the treatment of various diseases including nephrological disorders. They are known to affect immunological cells, effectively treating many autoimmune and inflammatory processes. Furthermore, there is a growing body of evidence demonstrating the potent role of [...] Read more.
Glucocorticoids, as multifunctional hormones, are widely used in the treatment of various diseases including nephrological disorders. They are known to affect immunological cells, effectively treating many autoimmune and inflammatory processes. Furthermore, there is a growing body of evidence demonstrating the potent role of glucocorticoids in non-immune cells such as podocytes. Moreover, novel data show additional pathways and processes affected by glucocorticoids, such as the Wnt pathway or autophagy. The endothelium is currently considered as a key organ in the regulation of numerous kidney functions such as glomerular filtration, vascular tone and the regulation of inflammation and coagulation. In this review, we analyse the literature concerning the effects of endothelial glucocorticoid receptor signalling on kidney function in health and disease, with special focus on hypertension, diabetic kidney disease, glomerulopathies and chronic kidney disease. Recent studies demonstrate the potential role of endothelial GR in the prevention of fibrosis of kidney tissue and cell metabolism through Wnt pathways, which could have a protective effect against disease progression. Another important aspect covered in this review is blood pressure regulation though GR and eNOS. We also briefly cover potential therapies that might affect the endothelial glucocorticoid receptor and its possible clinical implications, with special interest in selective or local GR stimulation and potential mitigation of GC treatment side effects. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

20 pages, 1057 KiB  
Review
Molecular Mechanisms of Mesenchymal Stem Cell-Based Therapy in Acute Kidney Injury
by Pei-Wen Lee, Bo-Sheng Wu, Chih-Yu Yang and Oscar Kuang-Sheng Lee
Int. J. Mol. Sci. 2021, 22(21), 11406; https://doi.org/10.3390/ijms222111406 - 22 Oct 2021
Cited by 13 | Viewed by 3681
Abstract
Acute kidney injury (AKI) causes a lot of harm to human health but is treated by only supportive therapy in most cases. Recent evidence shows that mesenchymal stem cells (MSCs) benefit kidney regeneration through releasing paracrine factors and extracellular vesicles (EVs) to the [...] Read more.
Acute kidney injury (AKI) causes a lot of harm to human health but is treated by only supportive therapy in most cases. Recent evidence shows that mesenchymal stem cells (MSCs) benefit kidney regeneration through releasing paracrine factors and extracellular vesicles (EVs) to the recipient kidney cells and are considered to be promising cellular therapy for AKI. To develop more efficient, precise therapies for AKI, we review the therapeutic mechanism of MSCs and MSC-derived EVs in AKI and look for a better understanding of molecular signaling and cellular communication between donor MSCs and recipient kidney cells. We also review recent clinical trials of MSC-EVs in AKI. This review summarizes the molecular mechanisms of MSCs’ therapeutic effects on kidney regeneration, expecting to comprehensively facilitate future clinical application for treating AKI. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

19 pages, 1748 KiB  
Review
Tubular Cell Cycle Response upon AKI: Revising Old and New Paradigms to Identify Novel Targets for CKD Prevention
by Letizia De Chiara, Carolina Conte, Giulia Antonelli and Elena Lazzeri
Int. J. Mol. Sci. 2021, 22(20), 11093; https://doi.org/10.3390/ijms222011093 - 14 Oct 2021
Cited by 20 | Viewed by 5269
Abstract
Acute kidney injury (AKI) is characterized by a rapid deterioration of kidney function, representing a global healthcare concern. In addition, AKI survivors frequently develop chronic kidney disease (CKD), contributing to a substantial proportion of disease burden globally. Yet, over the past 30 years, [...] Read more.
Acute kidney injury (AKI) is characterized by a rapid deterioration of kidney function, representing a global healthcare concern. In addition, AKI survivors frequently develop chronic kidney disease (CKD), contributing to a substantial proportion of disease burden globally. Yet, over the past 30 years, the burden of CKD has not declined to the same extent as many other important non-communicable diseases, implying a substantial deficit in the understanding of the disease progression. The assumption that the kidney response to AKI is based on a high proliferative potential of proximal tubular cells (PTC) caused a critical confounding factor, which has led to a limited development of strategies to prevent AKI and halt progression toward CKD. In this review, we discuss the latest findings on multiple mechanisms of response related to cell cycle behavior of PTC upon AKI, with a specific focus on their biological relevance. Collectively, we aim to (1) provide a new perspective on interpreting cell cycle progression of PTC in response to damage and (2) discuss how this knowledge can be used to choose the right therapeutic window of treatment for preserving kidney function while avoiding CKD progression. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

15 pages, 907 KiB  
Review
Extracellular Vesicles in Acute Kidney Injury and Clinical Applications
by Sekyung Oh and Sang-Ho Kwon
Int. J. Mol. Sci. 2021, 22(16), 8913; https://doi.org/10.3390/ijms22168913 - 18 Aug 2021
Cited by 18 | Viewed by 3977
Abstract
Acute kidney injury (AKI)––the sudden loss of kidney function due to tissue damage and subsequent progression to chronic kidney disease––has high morbidity and mortality rates and is a serious worldwide clinical problem. Current AKI diagnosis, which relies on measuring serum creatinine levels and [...] Read more.
Acute kidney injury (AKI)––the sudden loss of kidney function due to tissue damage and subsequent progression to chronic kidney disease––has high morbidity and mortality rates and is a serious worldwide clinical problem. Current AKI diagnosis, which relies on measuring serum creatinine levels and urine output, cannot sensitively and promptly report on the state of damage. To address the shortcomings of these traditional diagnosis tools, several molecular biomarkers have been developed to facilitate the identification and ensuing monitoring of AKI. Nanosized membrane-bound extracellular vesicles (EVs) in body fluids have emerged as excellent sources for discovering such biomarkers. Besides this diagnostic purpose, EVs are also being extensively exploited to deliver therapeutic macromolecules to damaged kidney cells to ameliorate AKI. Consequently, many successful AKI biomarker findings and therapeutic applications based on EVs have been made. Here, we review our understanding of how EVs can help with the early identification and accurate monitoring of AKI and be used therapeutically. We will further discuss where current EV-based AKI diagnosis and therapeutic applications fall short and where future innovations could lead us. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-18
Back to TopTop