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Molecular Mechanisms of Kidney Injury
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Molecular Mechanisms of Kidney Injury

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 17932

Special Issue Editors

Prof. Dr. Giuseppe Castellano

E-Mail Website
Guest Editor
Nephrology, Dialysis and Transplantation Unit, Università degli Studi di Foggia, Foggia, Italy
Interests: acute kidney injury; sepsis, renal transplantation; complement system; fibrosis and aging; dendritic cells
Special Issues, Collections and Topics in MDPI journals
Dr. Rossana Franzin

E-Mail Website
Guest Editor
Department of Emergency and Organ Transplantation, University of Bari, 70121 Bari, Italy
Interests: acute kidney injury; renal aging; complement system; renal transplantation; endothelial-to-mesenchymal transition
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Renal disease is defined as a heterogeneous group of disorders affecting kidney structure and function. Acute kidney injury (AKI) is a complex syndrome that occurs in critically ill patients and has different etiologies such as sepsis, ischemia reperfusion (I/R) injury, nephrotoxin exposition or major surgery. Other factors, including diabetic status, hypertension, hypoxia, activation of the complement system, can lead to progression of chronic nephropathies. In recent years, research efforts have led to the hypothesis that each type of kidney injury, occurring in distinct kidney compartments (on endothelium, tubular, mesangial cells and podocytes, M1/M2 macrophages), preferentially activates pathway involved in inflammation, premature aging, CKD progression or cellular regeneration and survival. In addition, soluble factors released by damaged renal cells, extracellular vesicles or resident progenitor/stem cells could have an effect on the regulation of a pro-injury microenvironment. Deciphering the molecular mechanism of action underlying kidney injury and repair would provide early biomarkers to predict clinical outcome and targeted therapies to prevent the injury and delay the progression to chronic kidney disease. In this Special Issue, we will publish original research and reviews that would offer new insights into the molecular mechanisms of renal damage with a close scrutiny on factors acting as bifurcation point versus progression to CKD or kidney repair. 

Prof. Dr. Giuseppe Castellano
Dr. Rossana Franzin
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • acute kidney injury
  • chronic kidney injury
  • endothelial dysfunction
  • DNA damage
  • cellular senescence
  • fibrosis
  • senescence
  • extracellular vesicles
  • regeneration progenitors
  • complement system
  • autophagy
  • macrophages

Related Special Issue

Published Papers (7 papers)

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Research

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22 pages, 6403 KiB  
Article
Differences in Immunohistochemical and Ultrastructural Features between Podocytes and Parietal Epithelial Cells (PECs) Are Observed in Developing, Healthy Postnatal, and Pathologically Changed Human Kidneys
by Marin Ogorevc, Ivona Kosovic, Natalija Filipovic, Ivana Bocina, Marija Juric, Benjamin Benzon, Snjezana Mardesic, Katarina Vukojevic, Marijan Saraga, Boris Kablar and Mirna Saraga-Babic
Int. J. Mol. Sci. 2022, 23(14), 7501; https://doi.org/10.3390/ijms23147501 - 6 Jul 2022
Cited by 5 | Viewed by 1654
Abstract
During human kidney development, cells of the proximal nephron gradually differentiate into podocytes and parietal epithelial cells (PECs). Podocytes are terminally differentiated cells that play a key role in both normal and pathological kidney function. Therefore, the potential of podocytes to regenerate or [...] Read more.
During human kidney development, cells of the proximal nephron gradually differentiate into podocytes and parietal epithelial cells (PECs). Podocytes are terminally differentiated cells that play a key role in both normal and pathological kidney function. Therefore, the potential of podocytes to regenerate or be replaced by other cell populations (PECs) is of great interest for the possible treatment of kidney diseases. In the present study, we analyzed the proliferation and differentiation capabilities of podocytes and PECs, changes in the expression pattern of nestin, and several early proteins including WNT4, Notch2, and Snail, as well as Ki-67, in tissues of developing, postnatal, and pathologically changed human kidneys by using immunohistochemistry and electron microscopy. Developing PECs showed a higher proliferation rate than podocytes, whereas nestin expression characterized only podocytes and pathologically changed kidneys. In the developing kidneys, WNT4 and Notch2 expression increased moderately in podocytes and strongly in PECs, whereas Snail increased only in PECs in the later fetal period. During human kidney development, WNT4, Notch2, and Snail are involved in early nephrogenesis control. In kidneys affected by congenital nephrotic syndrome of the Finnish type (CNF) and focal segmental glomerulosclerosis (FSGS), WNT4 decreased in both cell populations, whereas Notch2 decreased in FSGS. In contrast, Snail increased both in CNF and FSGS, whereas Notch2 increased only in CNF. Electron microscopy revealed cytoplasmic processes spanning the urinary space between the podocytes and PECs in developing and healthy postnatal kidneys, whereas the CNF and FSGS kidneys were characterized by numerous cellular bridges containing cells with strong expression of nestin and all analyzed proteins. Our results indicate that the mechanisms of gene control in nephrogenesis are reactivated under pathological conditions. These mechanisms could have a role in restoring glomerular integrity by potentially inducing the regeneration of podocytes from PECs. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury)
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12 pages, 3058 KiB  
Article
Endothelial ADAM17 Expression in the Progression of Kidney Injury in an Obese Mouse Model of Pre-Diabetes
by Vanesa Palau, Josué Jarrín, Sofia Villanueva, David Benito, Eva Márquez, Eva Rodríguez, María José Soler, Anna Oliveras, Javier Gimeno, Laia Sans, Marta Crespo, Julio Pascual, Clara Barrios and Marta Riera
Int. J. Mol. Sci. 2022, 23(1), 221; https://doi.org/10.3390/ijms23010221 - 25 Dec 2021
Cited by 4 | Viewed by 3370
Abstract
Disintegrin and metalloproteinase domain 17 (ADAM17) activates inflammatory and fibrotic processes through the shedding of various molecules such as Tumor Necrosis Factor-α (TNF-α) or Transforming Growht Factor-α (TGF-α). There is a well-recognised link between TNF-α, obesity, inflammation, and diabetes. In physiological situations, ADAM17 [...] Read more.
Disintegrin and metalloproteinase domain 17 (ADAM17) activates inflammatory and fibrotic processes through the shedding of various molecules such as Tumor Necrosis Factor-α (TNF-α) or Transforming Growht Factor-α (TGF-α). There is a well-recognised link between TNF-α, obesity, inflammation, and diabetes. In physiological situations, ADAM17 is expressed mainly in the distal tubular cell while, in renal damage, its expression increases throughout the kidney including the endothelium. The aim of this study was to characterize, for the first time, an experimental mouse model fed a high-fat diet (HFD) with a specific deletion of Adam17 in endothelial cells and to analyse the effects on different renal structures. Endothelial Adam17 knockout male mice and their controls were fed a high-fat diet, to induce obesity, or standard rodent chow, for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, macrophage infiltration, and galectin-3 levels were evaluated. Results showed that obese mice presented higher blood glucose levels, dysregulated glucose homeostasis, and higher body weight compared to control mice. In addition, obese wild-type mice presented an increased albumin-to-creatinine ratio; greater glomerular size and mesangial matrix expansion; and tubular fibrosis with increased galectin-3 expression. Adam17 deletion decreased the albumin-to-creatinine ratio, glomerular mesangial index, and tubular galectin-3 expression. Moreover, macrophage infiltration in the glomeruli of obese Adam17 knockout mice was reduced as compared to obese wild-type mice. In conclusion, the expression of ADAM17 in endothelial cells impacted renal inflammation, modulating the renal function and histology in an obese pre-diabetic mouse model. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury)
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19 pages, 3259 KiB  
Article
Interdependent Regulation of Polycystin Expression Influences Starvation-Induced Autophagy and Cell Death
by Jean-Paul Decuypere, Dorien Van Giel, Peter Janssens, Ke Dong, Stefan Somlo, Yiqiang Cai, Djalila Mekahli and Rudi Vennekens
Int. J. Mol. Sci. 2021, 22(24), 13511; https://doi.org/10.3390/ijms222413511 - 16 Dec 2021
Cited by 6 | Viewed by 2614
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by deficiency of polycystin-1 (PC1) or polycystin-2 (PC2). Altered autophagy has recently been implicated in ADPKD progression, but its exact regulation by PC1 and PC2 remains unclear. We therefore investigated cell death and survival [...] Read more.
Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by deficiency of polycystin-1 (PC1) or polycystin-2 (PC2). Altered autophagy has recently been implicated in ADPKD progression, but its exact regulation by PC1 and PC2 remains unclear. We therefore investigated cell death and survival during nutritional stress in mouse inner medullary collecting duct cells (mIMCDs), either wild-type (WT) or lacking PC1 (PC1KO) or PC2 (PC2KO), and human urine-derived proximal tubular epithelial cells (PTEC) from early-stage ADPKD patients with PC1 mutations versus healthy individuals. Basal autophagy was enhanced in PC1-deficient cells. Similarly, following starvation, autophagy was enhanced and cell death reduced when PC1 was reduced. Autophagy inhibition reduced cell death resistance in PC1KO mIMCDs to the WT level, implying that PC1 promotes autophagic cell survival. Although PC2 expression was increased in PC1KO mIMCDs, PC2 knockdown did not result in reduced autophagy. PC2KO mIMCDs displayed lower basal autophagy, but more autophagy and less cell death following chronic starvation. This could be reversed by overexpression of PC1 in PC2KO. Together, these findings indicate that PC1 levels are partially coupled to PC2 expression, and determine the transition from renal cell survival to death, leading to enhanced survival of ADPKD cells during nutritional stress. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury)
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15 pages, 3492 KiB  
Article
Paricalcitol Improves Hypoxia-Induced and TGF-β1-Induced Injury in Kidney Pericytes
by Jeong-Hoon Lim, Ju-Min Yook, Se-Hyun Oh, Soo-Jee Jeon, Hee Won Noh, Hee-Yeon Jung, Ji-Young Choi, Jang-Hee Cho, Chan-Duck Kim, Yong-Lim Kim and Sun-Hee Park
Int. J. Mol. Sci. 2021, 22(18), 9751; https://doi.org/10.3390/ijms22189751 - 9 Sep 2021
Cited by 5 | Viewed by 1943
Abstract
Recently, the role of kidney pericytes in kidney fibrosis has been investigated. This study aims to evaluate the effect of paricalcitol on hypoxia-induced and TGF-β1-induced injury in kidney pericytes. The primary cultured pericytes were pretreated with paricalcitol (20 ng/mL) for 90 min before [...] Read more.
Recently, the role of kidney pericytes in kidney fibrosis has been investigated. This study aims to evaluate the effect of paricalcitol on hypoxia-induced and TGF-β1-induced injury in kidney pericytes. The primary cultured pericytes were pretreated with paricalcitol (20 ng/mL) for 90 min before inducing injury, and then they were exposed to TGF-β1 (5 ng/mL) or hypoxia (1% O2 and 5% CO2). TGF-β1 increased α-SMA and other fibrosis markers but reduced PDGFRβ expression in pericytes, whereas paricalcitol reversed the changes. Paricalcitol inhibited the TGF-β1-induced cell migration of pericytes. Hypoxia increased TGF-β1, α-SMA and other fibrosis markers but reduced PDGFRβ expression in pericyte, whereas paricalcitol reversed them. Hypoxia activated the HIF-1α and downstream molecules including prolyl hydroxylase 3 and glucose transporter-1, whereas paricalcitol attenuated the activation of the HIF-1α-dependent molecules and TGF-β1/Smad signaling pathways in hypoxic pericytes. The gene silencing of HIF-1α vanished the hypoxia-induced TGF-β1, α-SMA upregulation, and PDGFRβ downregulation. The effect of paricalcitol on the HIF-1α-dependent changes of fibrosis markers was not significant after the gene silencing of HIF-1α. In addition, hypoxia aggravated the oxidative stress in pericytes, whereas paricalcitol reversed the oxidative stress by increasing the antioxidant enzymes in an HIF-1α-independent manner. In conclusion, paricalcitol improved the phenotype changes of pericyte to myofibroblast in TGF-β1-stimulated pericytes. In addition, paricalcitol improved the expression of fibrosis markers in hypoxia-exposed pericytes both in an HIF-1α-dependent and independent manner. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury)
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Review

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11 pages, 686 KiB  
Review
Human Stem Cell and Organoid Models to Advance Acute Kidney Injury Diagnostics and Therapeutics
by Naomi Pode-Shakked and Prasad Devarajan
Int. J. Mol. Sci. 2022, 23(13), 7211; https://doi.org/10.3390/ijms23137211 - 29 Jun 2022
Cited by 1 | Viewed by 2286
Abstract
Acute kidney injury (AKI) is an increasingly common problem afflicting all ages, occurring in over 20% of non-critically ill hospitalized patients and >30% of children and >50% of adults in critical care units. AKI is associated with serious short-term and long-term consequences, and [...] Read more.
Acute kidney injury (AKI) is an increasingly common problem afflicting all ages, occurring in over 20% of non-critically ill hospitalized patients and >30% of children and >50% of adults in critical care units. AKI is associated with serious short-term and long-term consequences, and current therapeutic options are unsatisfactory. Large gaps remain in our understanding of human AKI pathobiology, which have hindered the discovery of novel diagnostics and therapeutics. Although animal models of AKI have been extensively studied, these differ significantly from human AKI in terms of molecular and cellular responses. In addition, animal models suffer from interspecies differences, high costs and ethical considerations. Static two-dimensional cell culture models of AKI also have limited utility since they have focused almost exclusively on hypoxic or cytotoxic injury to proximal tubules alone. An optimal AKI model would encompass several of the diverse specific cell types in the kidney that could be targets of injury. Second, it would resemble the human physiological milieu as closely as possible. Third, it would yield sensitive and measurable readouts that are directly applicable to the human condition. In this regard, the past two decades have seen a dramatic shift towards newer personalized human-based models to study human AKI. In this review, we provide recent developments using human stem cells, organoids, and in silico approaches to advance personalized AKI diagnostics and therapeutics. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury)
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12 pages, 807 KiB  
Review
A Shared Nephroprotective Mechanism for Renin-Angiotensin-System Inhibitors, Sodium-Glucose Co-Transporter 2 Inhibitors, and Vasopressin Receptor Antagonists: Immunology Meets Hemodynamics
by Giovanna Capolongo, Giovambattista Capasso and Davide Viggiano
Int. J. Mol. Sci. 2022, 23(7), 3915; https://doi.org/10.3390/ijms23073915 - 1 Apr 2022
Cited by 9 | Viewed by 2751
Abstract
A major paradigm in nephrology states that the loss of filtration function over a long time is driven by a persistent hyperfiltration state of surviving nephrons. This hyperfiltration may derive from circulating immunological factors. However, some clue about the hemodynamic effects of these [...] Read more.
A major paradigm in nephrology states that the loss of filtration function over a long time is driven by a persistent hyperfiltration state of surviving nephrons. This hyperfiltration may derive from circulating immunological factors. However, some clue about the hemodynamic effects of these factors derives from the effects of so-called nephroprotective drugs. Thirty years after the introduction of Renin-Angiotensin-system inhibitors (RASi) into clinical practice, two new families of nephroprotective drugs have been identified: the sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the vasopressin receptor antagonists (VRA). Even though the molecular targets of the three-drug classes are very different, they share the reduction in the glomerular filtration rate (GFR) at the beginning of the therapy, which is usually considered an adverse effect. Therefore, we hypothesize that acute GFR decline is a prerequisite to obtaining nephroprotection with all these drugs. In this study, we reanalyze evidence that RASi, SGLT2i, and VRA reduce the eGFR at the onset of therapy. Afterward, we evaluate whether the extent of eGFR reduction correlates with their long-term efficacy. The results suggest that the extent of initial eGFR decline predicts the nephroprotective efficacy in the long run. Therefore, we propose that RASi, SGLT2i, and VRA delay kidney disease progression by controlling maladaptive glomerular hyperfiltration resulting from circulating immunological factors. Further studies are needed to verify their combined effects. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury)
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Other

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8 pages, 743 KiB  
Brief Report
Dynamics of Plasma and Urinary Extracellular DNA in Acute Kidney Injury
by Alexander Jančuška, Alena Potočárová, Alexandra Gaál Kovalčíková, Ľudmila Podracká, Janka Bábíčková, Peter Celec and Ľubomíra Tóthová
Int. J. Mol. Sci. 2022, 23(6), 3402; https://doi.org/10.3390/ijms23063402 - 21 Mar 2022
Cited by 6 | Viewed by 2287
Abstract
Early and reliable markers of acute kidney injury (AKI) are essential. One such candidate marker of tissue damage is extracellular DNA (ecDNA). The aim of our present study is to describe the unknown dynamics of ecDNA in an animal model of AKI. Glycerol-induced [...] Read more.
Early and reliable markers of acute kidney injury (AKI) are essential. One such candidate marker of tissue damage is extracellular DNA (ecDNA). The aim of our present study is to describe the unknown dynamics of ecDNA in an animal model of AKI. Glycerol-induced nephropathy was used to model AKI in adult male Wistar rats (n = 93). Blood and urine samples were collected 1, 3, and 24 h after model induction. Total ecDNA and its sub-cellular origin was assessed. In the plasma, total ecDNA and nuclear ecDNA were significantly increased in the AKI group already after 1 h (160% and 270%, respectively, p = 0.02 and p = 0.04). Both nuclear and mitochondrial ecDNA were higher after 3 h (180% and 170%, respectively, p = 0.002 and p = 0.005). Urinary ecDNA concentrations in the AKI group were significantly increased only 24 h after model induction (130% for total ecDNA, p = 0.009; 210% for nuclear ecDNA, p = 0.02; and 200% for mitochondrial ecDNA, p = 0.0009). Our results indicate that plasma ecDNA has the potential to serve as an early and sensitive, albeit non-specific marker of AKI. Further studies should elucidate the source of ecDNA and the dynamics of ecDNA in other animal models of AKI and patients with AKI. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury)
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