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Molecular Mechanisms of Kidney Injury and Repair

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

Deadline for manuscript submissions: closed (16 February 2020) | Viewed by 73931

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Special Issue Editor

Prof. Grazyna Nowak

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Guest Editor

Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, 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 Biomelecules seeks manuscripts that 1) elucidate cellular and molecular mechanisms and pathways mediating kidney injury and recovery, 2) identify molecular targets that are effective in preventing cell injury or promoting cell repair after injury, and 3) describe new animal models that could better represent these mechanisms in human kidenys. We encourage scientists working in this area of research to submit research articles, communications, or critical reviews that synthesize the current research 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. Grazyna Nowak
Guest Editor

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

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 models of kidney injury

Published Papers (10 papers)

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Research

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22 pages, 7439 KiB

Open AccessArticle

Deletion of VDAC1 Hinders Recovery of Mitochondrial and Renal Functions After Acute Kidney Injury

by Grazyna Nowak, Judit Megyesi and William J. Craigen

Biomolecules 2020, 10(4), 585; https://doi.org/10.3390/biom10040585 - 10 Apr 2020

Cited by 14 | Viewed by 2502

Abstract

Voltage-dependent anion channels (VDACs) constitute major transporters mediating bidirectional movement of solutes between cytoplasm and mitochondria. We aimed to determine if VDAC1 plays a role in recovery of mitochondrial and kidney functions after ischemia-induced acute kidney injury (AKI). Kidney function decreased after ischemia and recovered in wild-type (WT), but not in VDAC1-deficient mice. Mitochondrial maximum respiration, activities of respiratory complexes and F_oF₁-ATPase, and ATP content in renal cortex decreased after ischemia and recovered in WT mice. VDAC1 deletion reduced respiration and ATP content in non-injured kidneys. Further, VDAC1 deletion blocked return of activities of respiratory complexes and F_oF₁-ATPase, and recovery of respiration and ATP content after ischemia. Deletion of VDAC1 exacerbated ischemia-induced mitochondrial fission, but did not aggravate morphological damage to proximal tubules after ischemia. However, VDAC1 deficiency impaired recovery of kidney morphology and increased renal interstitial collagen accumulation. Thus, our data show a novel role for VDAC1 in regulating renal mitochondrial dynamics and recovery of mitochondrial function and ATP levels after AKI. We conclude that the presence of VDAC1 (1) stimulates capacity of renal mitochondria for respiration and ATP production, (2) reduces mitochondrial fission, (3) promotes recovery of mitochondrial function and dynamics, renal morphology, and kidney functions, and (4) increases survival after AKI. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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18 pages, 2426 KiB

Open AccessEditor’s ChoiceArticle

Proteomic Analysis of Human Serum from Patients with Chronic Kidney Disease

by Yulia Romanova, Alexander Laikov, Maria Markelova, Rania Khadiullina, Alfiz Makseev, Milausha Hasanova, Albert Rizvanov, Svetlana Khaiboullina and Ilnur Salafutdinov

Biomolecules 2020, 10(2), 257; https://doi.org/10.3390/biom10020257 - 7 Feb 2020

Cited by 32 | Viewed by 5675

Abstract

Chronic kidney disease (CKD) is an important public health problem in the world. The aim of our research was to identify novel potential serum biomarkers of renal injury. ELISA assay showed that cytokines and chemokines IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Eotaxin, FGFb, G-CSF, GM-CSF, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-1bb, RANTES, TNF-α and VEGF were significantly higher (R > 0.6, p value < 0.05) in the serum of patients with CKD compared to healthy subjects, and they were positively correlated with well-established markers (urea and creatinine). The multiple reaction monitoring (MRM) quantification method revealed that levels of HSP90B2, AAT, IGSF22, CUL5, PKCE, APOA4, APOE, APOA1, CCDC171, CCDC43, VIL1, Antigen KI-67, NKRF, APPBP2, CAPRI and most complement system proteins were increased in serum of CKD patients compared to the healthy group. Among complement system proteins, the C8G subunit was significantly decreased three-fold in patients with CKD. However, only AAT and HSP90B2 were positively correlated with well-established markers and, therefore, could be proposed as potential biomarkers for CKD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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17 pages, 3163 KiB

Open AccessEditor’s ChoiceArticle

Novel Variants of Angiotensin Converting Enzyme-2 of Shorter Molecular Size to Target the Kidney Renin Angiotensin System

by Jan Wysocki, Arndt Schulze and Daniel Batlle

Biomolecules 2019, 9(12), 886; https://doi.org/10.3390/biom9120886 - 17 Dec 2019

Cited by 39 | Viewed by 6883

Abstract

ACE2 is a monocarboxypeptidase which generates Angiotensin (1–7) from Angiotensin II (1–8). Attempts to target the kidney Renin Angiotensin System using native ACE2 to treat kidney disease are hampered by its large molecular size, 100 kDa, which precludes its glomerular filtration and subsequent tubular uptake. Here, we show that both urine and kidney lysates are capable of digesting native ACE2 into shorter proteins of ~60–75 kDa and then demonstrate that they are enzymatically very active. We then truncated the native ACE2 by design from the C-terminus to generate two short recombinant (r)ACE2 variants (1-605 and 1-619AA). These two truncates have a molecular size of ~70 kDa, as expected from the amino acid sequence and as shown by Western blot. ACE2 enzyme activity, measured using a specific substrate, was higher than that of the native rACE2 (1-740 AA). When infused to mice with genetic ACE2 deficiency, a single i.v. injection of 1-619 resulted in detectable ACE2 activity in urine, whereas infusion of the native ACE2 did not. Moreover, ACE2 activity was recovered in harvested kidneys from ACE2-deficient mice infused with 1-619, but not in controls (23.1 ± 4.3 RFU/µg creatinine/h and 1.96 ± 0.73 RFU/µg protein/hr, respectively). In addition, the kidneys of ACE2-null mice infused with 1-619 studied ex vivo formed more Ang (1–7) from exogenous Ang II than those infused with vehicle (AUC 8555 ± 1933 vs. 3439 ± 753 ng/mL, respectively, p < 0.05) further demonstrating the functional effect of increasing kidney ACE2 activity after the infusion of our short ACE2 1-619 variant. We conclude that our novel short recombinant ACE2 variants undergo glomerular filtration, which is associated with kidney uptake of enzymatically active proteins that can enhance the formation of Ang (1–7) from Ang II. These small ACE2 variants may offer a potentially useful approach to target kidney RAS overactivity to combat kidney injury. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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23 pages, 3630 KiB

Open AccessArticle

Specific BK Channel Activator NS11021 Protects Rat Renal Proximal Tubular Cells from Cold Storage—Induced Mitochondrial Injury In Vitro

by Stephen Shrum, Nancy J. Rusch and Lee Ann MacMillan-Crow

Biomolecules 2019, 9(12), 825; https://doi.org/10.3390/biom9120825 - 4 Dec 2019

Cited by 13 | Viewed by 2819

Abstract

Kidneys from deceased donors used for transplantation are placed in cold storage (CS) solution during the search for a matched recipient. However, CS causes mitochondrial injury, which may exacerbate renal graft dysfunction. Here, we explored whether adding NS11021, an activator of the mitochondrial big-conductance calcium-activated K⁺ (mitoBK) channel, to CS solution can mitigate CS-induced mitochondrial injury. We used normal rat kidney proximal tubular epithelial (NRK) cells as an in vitro model of renal cold storage (18 h) and rewarming (2 h) (CS + RW). Western blots detected the pore-forming α subunit of the BK channel in mitochondrial fractions from NRK cells. The fluorescent K⁺-binding probe, PBFI-AM, revealed that isolated mitochondria from NRK cells exhibited mitoBK-mediated K⁺ uptake, which was impaired ~70% in NRK cells subjected to CS + RW compared to control NRK cells maintained at 37 °C. Importantly, the addition of 1 μM NS11021 to CS solution prevented CS + RW-induced impairment of mitoBK-mediated K⁺ uptake. The NS11021–treated NRK cells also exhibited less cell death and mitochondrial injury after CS + RW, including mitigated mitochondrial respiratory dysfunction, depolarization, and superoxide production. In summary, these new data show for the first time that mitoBK channels may represent a therapeutic target to prevent renal CS-induced injury. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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20 pages, 5832 KiB

Open AccessArticle

All-Trans Retinoic Acid Attenuates Fibrotic Processes by Downregulating TGF-β1/Smad3 in Early Diabetic Nephropathy

by Edith Sierra-Mondragon, Rafael Rodríguez-Muñoz, Carmen Namorado-Tonix, Eduardo Molina-Jijon, Daniel Romero-Trejo, Jose Pedraza-Chaverri and Jose L. Reyes

Biomolecules 2019, 9(10), 525; https://doi.org/10.3390/biom9100525 - 25 Sep 2019

Cited by 31 | Viewed by 4302

Abstract

Diabetic nephropathy (DN) involves damage associated to hyperglycemia and oxidative stress. Renal fibrosis is a major pathologic feature of DN. The aim of this study was to evaluate anti-fibrogenic and renoprotective effects of all-trans retinoic acid (ATRA) in isolated glomeruli and proximal tubules of diabetic rats. Diabetes was induced by single injection of streptozotocin (STZ, 60 mg/Kg). ATRA (1 mg/Kg) was administered daily by gavage, from days 3–21 after STZ injection. ATRA attenuated kidney injury through the reduction of proteinuria, renal hypertrophy, increase in natriuresis, as well as early markers of damage such as β2-microglobulin, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL). The following parameters increased: macrophage infiltration, localization of alpha-smooth muscle actin (αSMA)-positive cells in renal tissue, and pro-fibrotic proteins such as transforming growth factor-β (TGF-β1), laminin beta 1 (LAM-β1), and collagens IV and I. Remarkably, ATRA treatment ameliorated these alterations and attenuated expression and nuclear translocation of Smad3, with increment of glomerular and tubular Smad7. The diabetic condition decreased expression of retinoic acid receptor alpha (RAR-α) through phosphorylation in serine residues mediated by the activation of c-Jun N-terminal kinase (JNK). ATRA administration restored the expression of RAR-α and inhibited direct interactions of JNK/RAR-α. ATRA prevented fibrogenesis through down-regulation of TGF-β1/Smad3 signaling. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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13 pages, 6071 KiB

Open AccessArticle

Mechanisms of Fasting-Mediated Protection against Renal Injury and Fibrosis Development after Ischemic Acute Kidney Injury

by Pedro Rojas-Morales, Edilia Tapia, Juan Carlos León-Contreras, Susana González-Reyes, Angélica Saraí Jiménez-Osorio, Joyce Trujillo, Natalia Pavón, Jessica Granados-Pineda, Rogelio Hernández-Pando, Laura Gabriela Sánchez-Lozada, Horacio Osorio-Alonso and José Pedraza-Chaverri

Biomolecules 2019, 9(9), 404; https://doi.org/10.3390/biom9090404 - 22 Aug 2019

Cited by 14 | Viewed by 4314

Abstract

Ischemia-reperfusion injury of the kidney may lead to renal fibrosis through a combination of several mechanisms. We recently demonstrated that fasting protects the rat kidney against oxidative stress and mitochondrial dysfunction in early acute kidney injury, and also against fibrosis development. Here we show that preoperative fasting preserves redox status and mitochondrial homeostasis at the chronic phase of damage after severe ischemia. Also, the protective effect of fasting coincides with the suppression of inflammation and endoplasmic reticulum stress, as well as the down-regulation of the mechanistic target of rapamycin (mTOR) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways in the fibrotic kidney. Our results demonstrate that fasting targets multiple pathophysiological mechanisms to prevent renal fibrosis and damage that results after renal ischemia-reperfusion injury. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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15 pages, 4623 KiB

Open AccessArticle

Microparticles as Potential Mediators of High Glucose-Induced Renal Cell Injury

by Sreenithya Ravindran, Mazhar Pasha, Abdelali Agouni and Shankar Munusamy

Biomolecules 2019, 9(8), 348; https://doi.org/10.3390/biom9080348 - 6 Aug 2019

Cited by 15 | Viewed by 4046

Abstract

Diabetic nephropathy (DN) is the most common cause of chronic kidney disease worldwide. Activation of signaling pathways such as the mammalian target of rapamycin (mTOR), extracellular signal-regulated kinases (ERK), endoplasmic reticulum (ER) stress, transforming growth factor-beta (TGF-β), and epithelial-mesenchymal transition (EMT), are thought to play a significant role in the etiology of DN. Microparticles (MPs), the small membrane vesicles containing bioactive signals shed by cells upon activation or during apoptosis, are elevated in diabetes and were identified as biomarkers in DN. However, their exact role in the pathophysiology of DN remains unclear. Here, we examined the effect of MPs shed from renal proximal tubular cells (RPTCs) exposed to high glucose conditions on naïve RPTCs in vitro. Our results showed significant increases in the levels of phosphorylated forms of 4E-binding protein 1 and ERK1/2 (the downstream targets of mTOR and ERK pathways), phosphorylated-eIF2α (an ER stress marker), alpha smooth muscle actin (an EMT marker), and phosphorylated-SMAD2 and nuclear translocation of SMAD4 (markers of TGF-β signaling). Together, our findings indicate that MPs activate key signaling pathways in RPTCs under high glucose conditions. Pharmacological interventions to inhibit shedding of MPs from RPTCs might serve as an effective strategy to prevent the progression of DN. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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Review

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24 pages, 1776 KiB

Open AccessEditor’s ChoiceReview

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

by Miguel Fontecha-Barriuso, Diego Martin-Sanchez, Julio Manuel Martinez-Moreno, Maria Monsalve, Adrian Mario Ramos, Maria Dolores Sanchez-Niño, Marta Ruiz-Ortega, Alberto Ortiz and Ana Belen Sanz

Biomolecules 2020, 10(2), 347; https://doi.org/10.3390/biom10020347 - 24 Feb 2020

Cited by 117 | Viewed by 19294

Abstract

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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35 pages, 1809 KiB

Open AccessReview

Autophagy Function and Regulation in Kidney Disease

by Gur P. Kaushal, Kiran Chandrashekar, Luis A. Juncos and Sudhir V. Shah

Biomolecules 2020, 10(1), 100; https://doi.org/10.3390/biom10010100 - 7 Jan 2020

Cited by 65 | Viewed by 8301

Abstract

Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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28 pages, 3159 KiB

Open AccessReview

Unilateral Ureteral Obstruction as a Model to Investigate Fibrosis-Attenuating Treatments

by Elena Martínez-Klimova, Omar Emiliano Aparicio-Trejo, Edilia Tapia and José Pedraza-Chaverri

Biomolecules 2019, 9(4), 141; https://doi.org/10.3390/biom9040141 - 8 Apr 2019

Cited by 175 | Viewed by 14669

Abstract

Renal fibrosis is the common pathway for most forms of progressive renal disease. The Unilateral Ureteral Obstruction (UUO) model is used to cause renal fibrosis, where the primary feature of UUO is tubular injury as a result of obstructed urine flow. Furthermore, experimental UUO in rodents is believed to mimic human chronic obstructive nephropathy in an accelerated manner. Renal fibrosis is the common pathway for most forms of progressive renal disease. Removing the obstruction may not be sufficient to reverse fibrosis, so an accompanying treatment may be of benefit. In this review, we have done a revision on treatments shown to ameliorate fibrosis in the context of the UUO experimental model. The treatments inhibit the production of fibrotic and inflammatory proteins such as Transforming Growth Factor β1 (TGF-β₁), Tumor Necrosis Factor α (TNF-α), collagen and fibronectin, Heat Shock Protein 47 (HSP47), suppress the proliferation of fibroblasts, prevent epithelial-to-mesenchymal transition, reduce oxidative stress, inhibit the action of the Nuclear Factor κB (NF-κB), reduce the phosphorylation of mothers against decapentaplegic homolog (SMAD) family members 2 and 3 (Smad2/3) or Mitogen-Activated Protein Kinases (MAPKs), inhibit the activation of the renin-angiotensin system. Summaries of the UUO experimental methods and alterations observed in the UUO experiments are included. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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