International Journal of Molecular Sciences

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21 pages, 5284 KiB

Open AccessArticle

Cell Profiling of Acute Kidney Injury to Chronic Kidney Disease Reveals Novel Oxidative Stress Characteristics in the Failed Repair of Proximal Tubule Cells

by Zhixiang Yu, Ying Zhou, Yuzhan Zhang, Xiaoxuan Ning, Tian Li, Lei Wei, Yingxue Wang, Xiao Bai and Shiren Sun

Int. J. Mol. Sci. 2023, 24(14), 11617; https://doi.org/10.3390/ijms241411617 - 18 Jul 2023

Cited by 3 | Viewed by 2453

Abstract

Chronic kidney disease (CKD) is a major public health issue around the world. A significant number of CKD patients originates from acute kidney injury (AKI) patients, namely “AKI–CKD”. CKD is significantly related to the consequences of AKI. Damaged renal proximal tubular (PT) cell [...] Read more.

Chronic kidney disease (CKD) is a major public health issue around the world. A significant number of CKD patients originates from acute kidney injury (AKI) patients, namely “AKI–CKD”. CKD is significantly related to the consequences of AKI. Damaged renal proximal tubular (PT) cell repair has been widely confirmed to indicate the renal prognosis of AKI. Oxidative stress is a key damage-associated factor and plays a significant role throughout the development of AKI and CKD. However, the relationships between AKI–CKD progression and oxidative stress are not totally clear and the underlying mechanisms in “AKI–CKD” remain indistinct. In this research, we constructed unilateral ischemia–reperfusion injury (UIRI)-model mice and performed single-nucleus RNA sequencing (snRNA-seq) of the kidney samples from UIRI and sham mice. We obtained our snRNA-seq data and validated the findings based on the joint analysis of public databases, as well as a series of fundamental experiments. Proximal tubular cells associated with failed repair express more complete senescence and oxidative stress characteristics compared to other subgroups. Furthermore, oxidative stress-related transcription factors, including Stat3 and Dnmt3a, are significantly more active under the circumstance of failed repair. What is more, we identified abnormally active intercellular communication between PT cells associated with failed repair and macrophages through the APP–CD74 pathway. More notably, we observed that the significantly increased expression of CD74 in hypoxia-treated TECs (tubular epithelial cells) was dependent on adjacently infiltrated macrophages, which was essential for the further deterioration of failed repair in PT cells. This research provides a novel understanding of the process of AKI to CKD progression, and the oxidative stress-related characteristics that we identified might represent a potentially novel therapeutic strategy against AKI. Full article

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

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13 pages, 2618 KiB

Open AccessArticle

Enhanced Levels of Glycosphingolipid GM3 Delay the Progression of Diabetic Nephropathy

by Shokichi Naito, Kenichi Nakayama and Nagako Kawashima

Int. J. Mol. Sci. 2023, 24(14), 11355; https://doi.org/10.3390/ijms241411355 - 12 Jul 2023

Cited by 3 | Viewed by 1527

Abstract

We recently found that albuminuria levels in patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) inversely correlate with glycosphingolipid GM3 expression levels in glomerular podocytes. Moreover, we showed enhanced expression of GM3 via activation of the GM3 synthase gene upon [...] Read more.

We recently found that albuminuria levels in patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) inversely correlate with glycosphingolipid GM3 expression levels in glomerular podocytes. Moreover, we showed enhanced expression of GM3 via activation of the GM3 synthase gene upon administration of valproic acid (VPA) is effective in suppressing albuminuria and podocyte injury in mice with anti-nephrin antibody-induced podocytopathy. However, the therapeutic effect of GM3 on diabetic nephropathy, which is the most common underlying disease in patients undergoing dialysis and with podocyte injury, remains unclear. Here, we investigated the therapeutic effect of enhanced GM3 expression via VPA on podocyte injury using streptozotocin-induced diabetic nephropathy model mice. Administration of VPA clearly decreased levels of albuminuria and glomerular lesions and inhibited the loss of podocytes and expansion in the mesangial area. Furthermore, we found that albuminuria levels in patients with diabetic nephropathy inversely correlate with the expression of GM3 in podocytes. These results indicate that maintaining GM3 expression in podocytes by administration of VPA may be effective in treating not only podocyte injury, such as MCD and FSGS, but also the late stage of diabetic nephropathy. Full article

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

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14 pages, 1878 KiB

Open AccessArticle

Effects of a High-Protein Diet on Kidney Injury under Conditions of Non-CKD or CKD in Mice

by Shohei Tanaka, Hiromichi Wakui, Kengo Azushima, Shunichiro Tsukamoto, Takahiro Yamaji, Shingo Urate, Toru Suzuki, Eriko Abe, Shinya Taguchi, Takayuki Yamada, Ryu Kobayashi, Tomohiko Kanaoka, Daisuke Kamimura, Sho Kinguchi, Masahito Takiguchi, Kengo Funakoshi, Akio Yamashita, Tomoaki Ishigami and Kouichi Tamura

Int. J. Mol. Sci. 2023, 24(9), 7778; https://doi.org/10.3390/ijms24097778 - 24 Apr 2023

Cited by 5 | Viewed by 5792

Abstract

Considering the prevalence of obesity and global aging, the consumption of a high-protein diet (HPD) may be advantageous. However, an HPD aggravates kidney dysfunction in patients with chronic kidney disease (CKD). Moreover, the effects of an HPD on kidney function in healthy individuals [...] Read more.

Considering the prevalence of obesity and global aging, the consumption of a high-protein diet (HPD) may be advantageous. However, an HPD aggravates kidney dysfunction in patients with chronic kidney disease (CKD). Moreover, the effects of an HPD on kidney function in healthy individuals are controversial. In this study, we employed a remnant kidney mouse model as a CKD model and aimed to evaluate the effects of an HPD on kidney injury under conditions of non-CKD and CKD. Mice were divided into four groups: a sham surgery (sham) + normal diet (ND) group, a sham + HPD group, a 5/6 nephrectomy (Nx) + ND group and a 5/6 Nx + HPD group. Blood pressure, kidney function and kidney tissue injury were compared after 12 weeks of diet loading among the four groups. The 5/6 Nx groups displayed blood pressure elevation, kidney function decline, glomerular injury and tubular injury compared with the sham groups. Furthermore, an HPD exacerbated glomerular injury only in the 5/6 Nx group; however, an HPD did not cause kidney injury in the sham group. Clinical application of these results suggests that patients with CKD should follow a protein-restricted diet to prevent the exacerbation of kidney injury, while healthy individuals can maintain an HPD without worrying about the adverse effects. Full article

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

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13 pages, 5244 KiB

Open AccessArticle

Folic Acid Ameliorates Renal Injury in Experimental Obstructive Nephropathy: Role of Glycine N-Methyltransferase

by Ko-Lin Kuo, Chin-Wei Chiang, Yi-Ming Arthur Chen, Chih-Chin Yu and Tzong-Shyuan Lee

Int. J. Mol. Sci. 2023, 24(7), 6859; https://doi.org/10.3390/ijms24076859 - 6 Apr 2023

Cited by 1 | Viewed by 2523

Abstract

Folic acid exerts both anti-inflammatory and antifibrotic effects. Glycine N-methyltransferase (GNMT), the major folic acid-binding protein in the liver, is a crucial enzyme that regulates the cellular methylation process by maintaining S-adenosylmethionine levels. However, as yet neither the therapeutic effects of folic acid [...] Read more.

Folic acid exerts both anti-inflammatory and antifibrotic effects. Glycine N-methyltransferase (GNMT), the major folic acid-binding protein in the liver, is a crucial enzyme that regulates the cellular methylation process by maintaining S-adenosylmethionine levels. However, as yet neither the therapeutic effects of folic acid in renal fibrosis nor whether GNMT is involved in these folic acid-associated mechanisms has been investigated. First, the expression of GNMT was examined in human kidneys with or without obstructive nephropathy. Later, wild-type and GNMT knockout (GNMT^−/−) mice were subjected to unilateral ureteral obstruction (UUO) and then treated with either folic acid or vehicle for 14 days. Renal tubular injury, inflammation, fibrosis, and autophagy were evaluated by histological analysis and Western blotting. We observed increased expression of GNMT in humans with obstructive nephropathy. Furthermore, UUO significantly increased the expression of GNMT in mice; in addition, it caused renal injury as well as the development of both hydronephrosis and tubular injury. These were all alleviated by folic acid treatment. In contrast, GNMT^−/− mice exhibited exacerbated UUO-induced renal injury, but the protective effect of folic acid was not observed in GNMT^−/− mice. We propose a novel role for folic acid in the treatment of renal fibrosis, which indicates that GNMT may be a therapeutic target. Full article

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

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15 pages, 696 KiB

Open AccessArticle

Longitudinal Analysis of Urinary Cytokines and Biomarkers in COVID-19 Patients with Subclinical Acute Kidney Injury

by Gustavo Casas-Aparicio, Claudia Alvarado-de la Barrera, David Escamilla-Illescas, Isabel León-Rodríguez, Perla Mariana Del Río-Estrada, Mauricio González-Navarro, Natalia Calderón-Dávila, Rossana Olmedo-Ocampo, Manuel Castillejos-López, Liliana Figueroa-Hernández, Amy B. Peralta-Prado, Yara Luna-Villalobos, Elvira Piten-Isidro, Paola Fernández-Campos, Alejandro Juárez-Díaz, Karolina Piekarska and Santiago Ávila-Ríos

Int. J. Mol. Sci. 2022, 23(23), 15419; https://doi.org/10.3390/ijms232315419 - 6 Dec 2022

Cited by 4 | Viewed by 2068

Abstract

In hospitalized COVID-19 patients, disease progression leading to acute kidney injury (AKI) may be driven by immune dysregulation. We explored the role of urinary cytokines and their relationship with kidney stress biomarkers in COVID-19 patients before and after the development of AKI. Of [...] Read more.

In hospitalized COVID-19 patients, disease progression leading to acute kidney injury (AKI) may be driven by immune dysregulation. We explored the role of urinary cytokines and their relationship with kidney stress biomarkers in COVID-19 patients before and after the development of AKI. Of 51 patients, 54.9% developed AKI. The principal component analysis indicated that in subclinical AKI, epidermal growth factor (EGF) and interferon (IFN)-α were associated with a lower risk of AKI, while interleukin-12 (IL-12) and macrophage inflammatory protein (MIP)-1β were associated with a higher risk of AKI. After the manifestation of AKI, EGF and IFN-α remained associated with a lower risk of AKI, while IL-1 receptor (IL-1R), granulocyte-colony stimulating factor (G-CSF), interferon-gamma-inducible protein 10 (IP-10) and IL-5 were associated with a higher risk of AKI. EGF had an inverse correlation with kidney stress biomarkers. Subclinical AKI was characterized by a significant up-regulation of kidney stress biomarkers and proinflammatory cytokines. The lack of EGF regenerative effects and IFN-α antiviral activity seemed crucial for renal disease progression. AKI involved a proinflammatory urinary cytokine storm. Full article

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

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12 pages, 2686 KiB

Open AccessArticle

Interleukin-10 Protects against Ureteral Obstruction-Induced Kidney Fibrosis by Suppressing Endoplasmic Reticulum Stress and Apoptosis

by Kyongjin Jung, Taejin Lee, Jooyoung Kim, Eongi Sung and Inhwan Song

Int. J. Mol. Sci. 2022, 23(18), 10702; https://doi.org/10.3390/ijms231810702 - 14 Sep 2022

Cited by 11 | Viewed by 2072

Abstract

Fibrosis is a common final pathway of chronic kidney disease, which is a major incurable disease. Although fibrosis has an irreversible pathophysiology, the molecular and cellular mechanisms responsible remain unclear and no specific treatment is available to halt the progress of renal fibrosis. [...] Read more.

Fibrosis is a common final pathway of chronic kidney disease, which is a major incurable disease. Although fibrosis has an irreversible pathophysiology, the molecular and cellular mechanisms responsible remain unclear and no specific treatment is available to halt the progress of renal fibrosis. Thus, an improved understanding of the cellular mechanism involved and a novel therapeutic approach are urgently required for end-stage renal disease (ESRD). We investigated the role played by interleukin-10 (IL-10, a potent anti-inflammatory cytokine) in kidney fibrosis and the mechanisms involved using IL-10^−/− mice and TCMK-1 cells (mouse kidney tubular epithelial cell line). Endoplasmic reticulum stress (ERS), apoptosis, and fibrosis in IL-10^−/− mice were more severe than in IL-10^+/+ mice after unilateral ureteral obstruction (UUO). The 4-Phenylbutyrate (an ERS inhibitor) treatment induced dramatic reductions in ERS, apoptosis, and fibrosis-associated factors in the renal tissues of IL-10^−/− mice, compared to wild-type controls after UUO. On the other hand, in cultured TCMK-1 cells, the ERS inducers (tunicamycin, thapsigargin, or brefeldin A) enhanced the expressions of proapoptotic and profibrotic factors, though these effects were mitigated by IL-10. These results were supported by the observation that IL-10 siRNA transfection aggravated tunicamycin-induced CHOP and a-SMA expressions in TCMK-1 cells. We conclude that the anti-fibrotic effects of IL-10 were attributable to the inhibition of ERS-mediated apoptosis and believe that the results of this study improve the understanding of the cellular mechanism responsible for fibrosis and aid in the development of novel therapeutic approaches. Full article

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

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18 pages, 3103 KiB

Open AccessArticle

Tubular IKKβ Deletion Alleviates Acute Ischemic Kidney Injury and Facilitates Tissue Regeneration

by Eileen Dahlke, Toni Engmann, Yaman Anan, Robert Häsler, Giovanni Solinas and Franziska Theilig

Int. J. Mol. Sci. 2022, 23(17), 10199; https://doi.org/10.3390/ijms231710199 - 5 Sep 2022

Viewed by 2369

Abstract

Acute kidney injury (AKI) is a common renal injury leading to relevant morbidity and mortality worldwide. Most of the clinical cases of AKI are caused by ischemia reperfusion (I/R) injury with renal ischemia injury followed by reperfusion injury and activation of the innate [...] Read more.

Acute kidney injury (AKI) is a common renal injury leading to relevant morbidity and mortality worldwide. Most of the clinical cases of AKI are caused by ischemia reperfusion (I/R) injury with renal ischemia injury followed by reperfusion injury and activation of the innate immune response converging to NF-ĸB pathway induction. Despite the clear role of NF-ĸB in inflammation, it has recently been acknowledged that NF-ĸB may impact other cell functions. To identify NF-ĸB function with respect to metabolism, vascular function and oxidative stress after I/R injury and to decipher in detail the underlying mechanism, we generated a transgenic mouse model with targeted deletion of IKKβ along the tubule and applied I/R injury followed by its analysis after 2 and 14 days after I/R injury. Tubular IKKβ deletion ameliorated renal function and reduced tissue damage. RNAseq data together with immunohistochemical, biochemical and morphometric analysis demonstrated an ameliorated vascular organization and mRNA expression profile for increased angiogenesis in mice with tubular IKKβ deletion at 2 days after I/R injury. RNAseq and protein analysis indicate an ameliorated metabolism, oxidative species handling and timely-adapted cell proliferation and apoptosis as well as reduced fibrosis in mice with tubular IKKβ deletion at 14 days after I/R injury. In conclusion, mice with tubular IKKβ deletion upon I/R injury display improved renal function and reduced tissue damage and fibrosis in association with improved vascularization, metabolism, reactive species disposal and fine-tuned cell proliferation. Full article

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

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15 pages, 3375 KiB

Open AccessArticle

Essential Roles of the Histone Demethylase KDM4C in Renal Development and Acute Kidney Injury

by Heng-Chih Pan, Yau-Hung Chen, Wei-Ching Fang, Vin-Cent Wu and Chiao-Yin Sun

Int. J. Mol. Sci. 2022, 23(16), 9318; https://doi.org/10.3390/ijms23169318 - 18 Aug 2022

Cited by 6 | Viewed by 2838

Abstract

Background: Lysine demethylase 4C (KDM4C) is a nuclear protein that is essential for histone modification and acts as an important regulator of several transcription factors. Previous studies have shown that KDM4C may also play a role in mediating stress responses. The purpose of [...] Read more.

Background: Lysine demethylase 4C (KDM4C) is a nuclear protein that is essential for histone modification and acts as an important regulator of several transcription factors. Previous studies have shown that KDM4C may also play a role in mediating stress responses. The purpose of this study was to examine the roles of KDM4C in kidney development and acute kidney injury (AKI). Methods: The effect of KDM4C on kidney development was assessed by comparing the kidney phenotype between 96 zebrafish embryos treated with kdm4c-morpholino oligonucleotide and 96 untreated zebrafish embryos. We further examined whether KDM4C is essential for maintaining cell survival in AKI. Cultured human renal tubular cells were used for the in vitro study. Wild-type and Kdm4c knockout mice (C57BL/6NTac-Kdm4ctm1a(KOMP)Wtsi) were divided into a sham group and model group, and then subjected to ischemic reperfusion kidney injury (IRI-AKI). Blood samples and kidneys were collected at different time points (day 3, day 7, day 14, and day 28) and were processed for in vivo studies (n = 8 in each group). Results: Kdm4c knockdown significantly decreased zebrafish embryo survival and impaired kidney development. The in vitro study showed that KDM4C inhibition by JIB04 significantly increased cellular apoptosis under oxidative stress conditions. KDM4C knockdown cells had impaired autophagy function under stress conditions. The IRI-AKI mice study showed that KDM4C protein levels dynamically changed and were significantly correlated with HIF-1α levels in AKI. Kdm4c^−/− mice had significantly more severe renal impairment and increased kidney fibrosis than the wild-type mice. Cytokine array results also indicated that the kidneys of Kdm4c^−/− mice had increased inflammation in AKI compared with the wild-type mice. Further RNA sequence analysis revealed that KDM4C may regulate transcription factors related to mitochondrial dynamics and function. Conclusions: Our study suggests that KDM4C may play a critical role in regulating mitochondria, which is related to a protective effect on maintaining cell survival in AKI. Full article

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

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14 pages, 2514 KiB

Open AccessArticle

Control of Directed Cell Migration after Tubular Cell Injury by Nucleotide Signaling

by Sabrina Gessler, Clara Guthmann, Vera Schuler, Miriam Lilienkamp, Gerd Walz and Toma Antonov Yakulov

Int. J. Mol. Sci. 2022, 23(14), 7870; https://doi.org/10.3390/ijms23147870 - 17 Jul 2022

Cited by 3 | Viewed by 2430

Abstract

Acute kidney injury (AKI) is a common complication of severe human diseases, resulting in increased morbidity and mortality as well as unfavorable long-term outcomes. Although the mammalian kidney is endowed with an amazing capacity to recover from AKI, little progress has been made [...] Read more.

Acute kidney injury (AKI) is a common complication of severe human diseases, resulting in increased morbidity and mortality as well as unfavorable long-term outcomes. Although the mammalian kidney is endowed with an amazing capacity to recover from AKI, little progress has been made in recent decades to facilitate recovery from AKI. To elucidate the early repair mechanisms after AKI, we employed the zebrafish pronephros injury model. Since damaged cells release large amounts of ATP and ATP-degradation products to signal apoptosis or necrosis to neighboring cells, we examined how depletion of purinergic and adenosine receptors impacts the directed cell migration that ensues immediately after a laser-induced tubular injury. We found that depletion of the zebrafish adenosine receptors adora1a, adora1b, adora2aa, and adora2ab significantly affected the repair process. Similar results were obtained after depletion of the purinergic p2ry2 receptor, which is highly expressed during zebrafish pronephros development. Released ATP is finally metabolized to inosine by adenosine deaminase. Depletion of zebrafish adenosine deaminases ada and ada2b interfered with the repair process; furthermore, combinations of ada and ada2b, or ada2a and ada2b displayed synergistic effects at low concentrations, supporting the involvement of inosine signaling in the repair process after a tubular injury. Our findings suggest that nucleotide-dependent signaling controls immediate migratory responses after tubular injury. Full article

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

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13 pages, 1312 KiB

Open AccessArticle

Development of a Mortality Prediction Model in Hospitalised SARS-CoV-2 Positive Patients Based on Routine Kidney Biomarkers

by Anna N. Boss, Abhirup Banerjee, Michail Mamalakis, Surajit Ray, Andrew J. Swift, Craig Wilkie, Joseph W. Fanstone, Bart Vorselaars, Joby Cole, Simonne Weeks and Louise S. Mackenzie

Int. J. Mol. Sci. 2022, 23(13), 7260; https://doi.org/10.3390/ijms23137260 - 30 Jun 2022

Cited by 3 | Viewed by 2313

Abstract

Acute kidney injury (AKI) is a prevalent complication in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive inpatients, which is linked to an increased mortality rate compared to patients without AKI. Here we analysed the difference in kidney blood biomarkers in SARS-CoV-2 positive [...] Read more.

Acute kidney injury (AKI) is a prevalent complication in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive inpatients, which is linked to an increased mortality rate compared to patients without AKI. Here we analysed the difference in kidney blood biomarkers in SARS-CoV-2 positive patients with non-fatal or fatal outcome, in order to develop a mortality prediction model for hospitalised SARS-CoV-2 positive patients. A retrospective cohort study including data from suspected SARS-CoV-2 positive patients admitted to a large National Health Service (NHS) Foundation Trust hospital in the Yorkshire and Humber regions, United Kingdom, between 1 March 2020 and 30 August 2020. Hospitalised adult patients (aged ≥ 18 years) with at least one confirmed positive RT-PCR test for SARS-CoV-2 and blood tests of kidney biomarkers within 36 h of the RT-PCR test were included. The main outcome measure was 90-day in-hospital mortality in SARS-CoV-2 infected patients. The logistic regression and random forest (RF) models incorporated six predictors including three routine kidney function tests (sodium, urea; creatinine only in RF), along with age, sex, and ethnicity. The mortality prediction performance of the logistic regression model achieved an area under receiver operating characteristic (AUROC) curve of 0.772 in the test dataset (95% CI: 0.694–0.823), while the RF model attained the AUROC of 0.820 in the same test cohort (95% CI: 0.740–0.870). The resulting validated prediction model is the first to focus on kidney biomarkers specifically on in-hospital mortality over a 90-day period. Full article

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

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14 pages, 2918 KiB

Open AccessArticle

Nitric Oxide Signalling in Descending Vasa Recta after Hypoxia/Re-Oxygenation

by Minze Xu, Falk-Bach Lichtenberger, Cem Erdoǧan, Enyin Lai, Pontus B. Persson, Andreas Patzak and Pratik H. Khedkar

Int. J. Mol. Sci. 2022, 23(13), 7016; https://doi.org/10.3390/ijms23137016 - 24 Jun 2022

Cited by 5 | Viewed by 2584

Abstract

Reduced renal medullary oxygen supply is a key factor in the pathogenesis of acute kidney injury (AKI). As the medulla exclusively receives blood through descending vasa recta (DVR), dilating these microvessels after AKI may help in renoprotection by restoring renal medullary blood flow. [...] Read more.

Reduced renal medullary oxygen supply is a key factor in the pathogenesis of acute kidney injury (AKI). As the medulla exclusively receives blood through descending vasa recta (DVR), dilating these microvessels after AKI may help in renoprotection by restoring renal medullary blood flow. We stimulated the NO-sGC-cGMP signalling pathway in DVR at three different levels before and after hypoxia/re-oxygenation (H/R). Rat DVR were isolated and perfused under isobaric conditions. The phosphodiesterase 5 (PDE5) inhibitor sildenafil (10⁻⁶ mol/L) impaired cGMP degradation and dilated DVR pre-constricted with angiotensin II (Ang II, 10⁻⁶ mol/L). Dilations by the soluble guanylyl cyclase (sGC) activator BAY 60-2770 as well as the nitric oxide donor sodium nitroprusside (SNP, 10⁻³ mol/L) were equally effective. Hypoxia (0.1% O₂) augmented DVR constriction by Ang II, thus potentially aggravating tissue hypoxia. H/R left DVR unresponsive to sildenafil, yet sGC activation by BAY 60-2770 effectively dilated DVR. Dilation to SNP under H/R is delayed. In conclusion, H/R renders PDE5 inhibition ineffective in dilating the crucial vessels supplying the area at risk for hypoxic damage. Stimulating sGC appears to be the most effective in restoring renal medullary blood flow after H/R and may prove to be the best target for maintaining oxygenation to this vulnerable area of the kidney. Full article

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

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Review

Jump to: Research

30 pages, 4994 KiB

Open AccessReview

Insights into the Molecular Mechanisms of NRF2 in Kidney Injury and Diseases

by Da-Wei Lin, Yung-Chien Hsu, Cheng-Chih Chang, Ching-Chuan Hsieh and Chun-Liang Lin

Int. J. Mol. Sci. 2023, 24(7), 6053; https://doi.org/10.3390/ijms24076053 - 23 Mar 2023

Cited by 19 | Viewed by 3612

Abstract

Redox is a constant phenomenon in organisms. From the signaling pathway transduction to the oxidative stress during the inflammation and disease process, all are related to reduction-oxidation (redox). Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor targeting many antioxidant genes. [...] Read more.

Redox is a constant phenomenon in organisms. From the signaling pathway transduction to the oxidative stress during the inflammation and disease process, all are related to reduction-oxidation (redox). Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor targeting many antioxidant genes. In non-stressed conditions, NRF2 maintains the hemostasis of redox with housekeeping work. It expresses constitutively with basal activity, maintained by Kelch-like-ECH-associated protein 1 (KEAP1)-associated ubiquitination and degradation. When encountering stress, it can be up-regulated by several mechanisms to exert its anti-oxidative ability in diseases or inflammatory processes to protect tissues and organs from further damage. From acute kidney injury to chronic kidney diseases, such as diabetic nephropathy or glomerular disease, many results of studies have suggested that, as a master of regulating redox, NRF2 is a therapeutic option. It was not until the early termination of the clinical phase 3 trial of diabetic nephropathy due to heart failure as an unexpected side effect that we renewed our understanding of NRF2. NRF2 is not just a simple antioxidant capacity but has pleiotropic activities, harmful or helpful, depending on the conditions and backgrounds. Full article

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

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17 pages, 885 KiB

Open AccessReview

Pre-Treatment of Transplant Donors with Hydrogen Sulfide to Protect against Warm and Cold Ischemia-Reperfusion Injury in Kidney and Other Transplantable Solid Organs

by Liam McFarlane, Pierce Nelson, George J. Dugbartey and Alp Sener

Int. J. Mol. Sci. 2023, 24(4), 3518; https://doi.org/10.3390/ijms24043518 - 9 Feb 2023

Cited by 5 | Viewed by 2828

Abstract

Ischemia-reperfusion injury (IRI), a pathological condition resulting from prolonged cessation and subsequent restoration of blood flow to a tissue, is an inevitable consequence of solid organ transplantation. Current organ preservation strategies, such as static cold storage (SCS), are aimed at reducing IRI. However, [...] Read more.

Ischemia-reperfusion injury (IRI), a pathological condition resulting from prolonged cessation and subsequent restoration of blood flow to a tissue, is an inevitable consequence of solid organ transplantation. Current organ preservation strategies, such as static cold storage (SCS), are aimed at reducing IRI. However, prolonged SCS exacerbates IRI. Recent research has examined pre-treatment approaches to more effectively attenuate IRI. Hydrogen sulfide (H₂S), the third established member of a family of gaseous signaling molecules, has been shown to target the pathophysiology of IRI and thus appears to be a viable candidate that can overcome the transplant surgeon’s enemy. This review discusses pre-treatment of renal grafts and other transplantable organs with H₂S to mitigate transplantation-induced IRI in animal models of transplantation. In addition, ethical principles of pre-treatment and potential applications of H₂S pre-treatment in the prevention of other IRI-associated conditions are discussed. Full article

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

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21 pages, 1983 KiB

Open AccessReview

Toll-like Receptor 4 in Acute Kidney Injury

by Patricia G. Vallés, Andrea Fernanda Gil Lorenzo, Rodrigo D. Garcia, Valeria Cacciamani, María Eugenia Benardon and Valeria Victoria Costantino

Int. J. Mol. Sci. 2023, 24(2), 1415; https://doi.org/10.3390/ijms24021415 - 11 Jan 2023

Cited by 11 | Viewed by 4313

Abstract

Acute kidney injury (AKI) is a common and devastating pathologic condition, associated with considerable high morbidity and mortality. Although significant breakthroughs have been made in recent years, to this day no effective pharmacological therapies for its treatment exist. AKI is known to be [...] Read more.

Acute kidney injury (AKI) is a common and devastating pathologic condition, associated with considerable high morbidity and mortality. Although significant breakthroughs have been made in recent years, to this day no effective pharmacological therapies for its treatment exist. AKI is known to be connected with intrarenal and systemic inflammation. The innate immune system plays an important role as the first defense response mechanism to tissue injury. Toll-like receptor 4 (TLR4) is a well-characterized pattern recognition receptor, and increasing evidence has shown that TLR4 mediated inflammatory response, plays a pivotal role in the pathogenesis of acute kidney injury. Pathogen-associated molecular patterns (PAMPS), which are the conserved microbial motifs, are sensed by these receptors. Endogenous molecules generated during tissue injury, and labeled as damage-associated molecular pattern molecules (DAMPs), also activate pattern recognition receptors, thereby offering an understanding of sterile types of inflammation. Excessive, uncontrolled and/or sustained activation of TLR4, may lead to a chronic inflammatory state. In this review we describe the role of TLR4, its endogenous ligands and activation in the inflammatory response to ischemic/reperfusion-induced AKI and sepsis-associated AKI. The potential regeneration signaling patterns of TLR4 in acute kidney injury, are also discussed. Full article

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

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15 pages, 1030 KiB

Open AccessReview

O-GlcNAcylation in Renal (Patho)Physiology

by Rodrigo P. Silva-Aguiar, Diogo B. Peruchetti, Ana Acacia S. Pinheiro, Celso Caruso-Neves and Wagner B. Dias

Int. J. Mol. Sci. 2022, 23(19), 11260; https://doi.org/10.3390/ijms231911260 - 24 Sep 2022

Cited by 9 | Viewed by 2853

Abstract

Kidneys maintain internal milieu homeostasis through a well-regulated manipulation of body fluid composition. This task is performed by the correlation between structure and function in the nephron. Kidney diseases are chronic conditions impacting healthcare programs globally, and despite efforts, therapeutic options for its [...] Read more.

Kidneys maintain internal milieu homeostasis through a well-regulated manipulation of body fluid composition. This task is performed by the correlation between structure and function in the nephron. Kidney diseases are chronic conditions impacting healthcare programs globally, and despite efforts, therapeutic options for its treatment are limited. The development of chronic degenerative diseases is associated with changes in protein O-GlcNAcylation, a post-translation modification involved in the regulation of diverse cell function. O-GlcNAcylation is regulated by the enzymatic balance between O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) which add and remove GlcNAc residues on target proteins, respectively. Furthermore, the hexosamine biosynthetic pathway provides the substrate for protein O-GlcNAcylation. Beyond its physiological role, several reports indicate the participation of protein O-GlcNAcylation in cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the impact of protein O-GlcNAcylation on physiological renal function, disease conditions, and possible future directions in the field. Full article

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

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Open AccessReview

From AKI to CKD: Maladaptive Repair and the Underlying Mechanisms

by Zhiwen Wang and Chun Zhang

Int. J. Mol. Sci. 2022, 23(18), 10880; https://doi.org/10.3390/ijms231810880 - 17 Sep 2022

Cited by 28 | Viewed by 5808

Abstract

Acute kidney injury (AKI) is defined as a pathological condition in which the glomerular filtration rate decreases rapidly over a short period of time, resulting in changes in the physiological function and tissue structure of the kidney. An increasing amount of evidence indicates [...] Read more.

Acute kidney injury (AKI) is defined as a pathological condition in which the glomerular filtration rate decreases rapidly over a short period of time, resulting in changes in the physiological function and tissue structure of the kidney. An increasing amount of evidence indicates that there is an inseparable relationship between acute kidney injury and chronic kidney disease (CKD). With the progress in research in this area, researchers have found that the recovery of AKI may also result in the occurrence of CKD due to its own maladaptation and other potential mechanisms, which involve endothelial cell injury, inflammatory reactions, progression to fibrosis and other pathways that promote the progress of the disease. Based on these findings, this review summarizes the occurrence and potential mechanisms of maladaptive repair in the progression of AKI to CKD and explores possible treatment strategies in this process so as to provide a reference for the inhibition of the progression of AKI to CKD. Full article

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

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