International Journal of Molecular Sciences

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Open AccessEditorial

Kidney Inflammation, Injury and Regeneration 2020

by Patrick C. Baer, Benjamin Koch and Helmut Geiger

Int. J. Mol. Sci. 2021, 22(11), 5589; https://doi.org/10.3390/ijms22115589 - 25 May 2021

Cited by 4 | Viewed by 2263

Abstract

The kidneys play a vital role in the basic physiological functions of the body [...] Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

Research

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14 pages, 3983 KiB

Open AccessArticle

Attenuating Effects of Dieckol on Hypertensive Nephropathy in Spontaneously Hypertensive Rats

by Myeongjoo Son, Seyeon Oh, Junwon Choi, Ji Tae Jang, Kuk Hui Son and Kyunghee Byun

Int. J. Mol. Sci. 2021, 22(8), 4230; https://doi.org/10.3390/ijms22084230 - 19 Apr 2021

Cited by 10 | Viewed by 2495

Abstract

Hypertension induces renal fibrosis or tubular interstitial fibrosis, which eventually results in end-stage renal disease. Epithelial-to-mesenchymal transition (EMT) is one of the underlying mechanisms of renal fibrosis. Though previous studies showed that Ecklonia cava extracts (ECE) and dieckol (DK) had inhibitory action on [...] Read more.

Hypertension induces renal fibrosis or tubular interstitial fibrosis, which eventually results in end-stage renal disease. Epithelial-to-mesenchymal transition (EMT) is one of the underlying mechanisms of renal fibrosis. Though previous studies showed that Ecklonia cava extracts (ECE) and dieckol (DK) had inhibitory action on angiotensin (Ang) I-converting enzyme, which converts Ang I to Ang II. It is known that Ang II is involved in renal fibrosis; however, it was not evaluated whether ECE or DK attenuated hypertensive nephropathy by decreasing EMT. In this study, the effect of ECE and DK on decreasing Ang II and its down signal pathway of angiotensin type 1 receptor (AT1R)/TGFβ/SMAD, which is related with the EMT and restoring renal function in spontaneously hypertensive rats (SHRs), was investigated. Either ECE or DK significantly decreased the serum level of Ang II in the SHRs. Moreover, the renal expression of AT1R/TGFβ/SMAD was decreased by the administration of either ECE or DK. The mesenchymal cell markers in the kidney of SHRs was significantly decreased by ECE or DK. The fibrotic tissue of the kidney of SHRs was also significantly decreased by ECE or DK. The ratio of urine albumin/creatinine of SHRs was significantly decreased by ECE or DK. Overall, the results of this study indicate that ECE and DK decreased the serum levels of Ang II and expression of AT1R/TGFβ/SMAD, and then decreased the EMT and renal fibrosis in SHRs. Furthermore, the decrease in EMT and renal fibrosis could lead to the restoration of renal function. It seems that ECE or DK could be beneficial for decreasing hypertensive nephropathy by decreasing EMT and renal fibrosis. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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17 pages, 3387 KiB

Open AccessArticle

Dual and Opposite Costimulatory Targeting with a Novel Human Fusion Recombinant Protein Effectively Prevents Renal Warm Ischemia Reperfusion Injury and Allograft Rejection in Murine Models

by Jordi Guiteras, Laura De Ramon, Elena Crespo, Nuria Bolaños, Silvia Barcelo-Batllori, Laura Martinez-Valenzuela, Pere Fontova, Marta Jarque, Alba Torija, Oriol Bestard, David Resina, Josep M Grinyó and Joan Torras

Int. J. Mol. Sci. 2021, 22(3), 1216; https://doi.org/10.3390/ijms22031216 - 26 Jan 2021

Cited by 4 | Viewed by 2576

Abstract

Many studies have shown both the CD28—D80/86 costimulatory pathway and the PD-1—PD-L1/L2 coinhibitory pathway to be important signals in modulating or decreasing the inflammatory profile in ischemia-reperfusion injury (IRI) or in a solid organ transplant setting. The importance of these two opposing pathways [...] Read more.

Many studies have shown both the CD28—D80/86 costimulatory pathway and the PD-1—PD-L1/L2 coinhibitory pathway to be important signals in modulating or decreasing the inflammatory profile in ischemia-reperfusion injury (IRI) or in a solid organ transplant setting. The importance of these two opposing pathways and their potential synergistic effect led our group to design a human fusion recombinant protein with CTLA4 and PD-L2 domains named HYBRI. The objective of our study was to determine the HYBRI binding to the postulated ligands of CTLA4 (CD80) and PD-L2 (PD-1) using the Surface Plasmon Resonance technique and to evaluate the in vivo HYBRI effects on two representative kidney inflammatory models—rat renal IRI and allogeneic kidney transplant. The Surface Plasmon Resonance assay demonstrated the avidity and binding of HYBRI to its targets. HYBRI treatment in the models exerted a high functional and morphological improvement. HYBRI produced a significant amelioration of renal function on day one and two after bilateral warm ischemia and on days seven and nine after transplant, clearly prolonging the animal survival in a life-sustaining renal allograft model. In both models, a significant reduction in histological damage and CD3 and CD68 infiltrating cells was observed. HYBRI decreased the circulating inflammatory cytokines and enriched the FoxP3 peripheral circulating, apart from reducing renal inflammation. In conclusion, the dual and opposite costimulatory targeting with that novel protein offers a good microenvironment profile to protect the ischemic process in the kidney and to prevent the kidney rejection, increasing the animal’s chances of survival. HYBRI largely prevents the progression of inflammation in these rat models. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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14 pages, 2685 KiB

Open AccessArticle

Inhibition of Yes-Associated Protein by Verteporfin Ameliorates Unilateral Ureteral Obstruction-Induced Renal Tubulointerstitial Inflammation and Fibrosis

by Jixiu Jin, Tian Wang, Woong Park, Wenjia Li, Won Kim, Sung Kwang Park and Kyung Pyo Kang

Int. J. Mol. Sci. 2020, 21(21), 8184; https://doi.org/10.3390/ijms21218184 - 31 Oct 2020

Cited by 23 | Viewed by 3444

Abstract

Yes-associated protein (YAP) activation after acute ischemic kidney injury might be related to interstitial fibrosis and impaired renal tubular regeneration. Verteporfin (VP) is a photosensitizer used in photodynamic therapy to treat age-related macular degeneration. In cancer cells, VP inhibits TEA domain family member [...] Read more.

Yes-associated protein (YAP) activation after acute ischemic kidney injury might be related to interstitial fibrosis and impaired renal tubular regeneration. Verteporfin (VP) is a photosensitizer used in photodynamic therapy to treat age-related macular degeneration. In cancer cells, VP inhibits TEA domain family member (TEAD)-YAP interactions without light stimulation. The protective role of VP in unilateral ureteral obstruction (UUO)-induced renal fibrosis and related mechanisms remains unclear. In this study, we investigate the protective effects of VP on UUO-induced renal tubulointerstitial inflammation and fibrosis and its regulation of the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. We find that VP decreased the UUO-induced increase in tubular injury, inflammation, and extracellular matrix deposition in mice. VP also decreased myofibroblast activation and proliferation in UUO kidneys and NRK-49F cells by modulating Smad2 and Smad3 phosphorylation. Therefore, YAP inhibition might have beneficial effects on UUO-induced tubulointerstitial inflammation and fibrosis by regulating the TGF-β1/Smad signaling pathway. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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14 pages, 5309 KiB

Open AccessArticle

B Cell Activating Factor (BAFF) Is Required for the Development of Intra-Renal Tertiary Lymphoid Organs in Experimental Kidney Transplantation in Rats

by Louisa Steines, Helen Poth, Marlene Herrmann, Antonia Schuster, Bernhard Banas and Tobias Bergler

Int. J. Mol. Sci. 2020, 21(21), 8045; https://doi.org/10.3390/ijms21218045 - 28 Oct 2020

Cited by 11 | Viewed by 3340

Abstract

Intra-renal tertiary lymphoid organs (TLOs) are associated with worsened outcome in kidney transplantation (Ktx). We used an anti-BAFF (B cell activating factor) intervention to investigate whether BAFF is required for TLO formation in a full MHC-mismatch Ktx model in rats. Rats received either [...] Read more.

Intra-renal tertiary lymphoid organs (TLOs) are associated with worsened outcome in kidney transplantation (Ktx). We used an anti-BAFF (B cell activating factor) intervention to investigate whether BAFF is required for TLO formation in a full MHC-mismatch Ktx model in rats. Rats received either therapeutic immunosuppression (no rejection, NR) or subtherapeutic immunosuppression (chronic rejection, CR) and were sacrificed on d56. One group additionally received an anti-BAFF antibody (CR + AB). Intra-renal T (CD3⁺) and B (CD20⁺) cells, their proliferation (Ki67⁺), and IgG⁺ plasma cells were analyzed by immunofluorescence microscopy. Formation of T and B cell zones and TLOs was assessed. Intra-renal expression of TLO-promoting factors, molecules of T:B crosstalk, and B cell differentiation was analyzed by qPCR. Intra-renal B and T cell zones and TLOs were detected in CR and were associated with elevated intra-renal mRNA expression of TLO-promoting factors, including CXCL13, CCL19, lymphotoxin-β, and BAFF. Intra-renal plasma cells were also elevated in CR. Anti-BAFF treatment significantly decreased intra-renal B cell zones and TLO, as well as intra-renal B cell-derived TLO-promoting factors and B cell differentiation markers. We conclude that BAFF-dependent intra-renal B cells promote TLO formation and advance local adaptive alloimmune responses in chronic rejection. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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18 pages, 3504 KiB

Open AccessArticle

The Crucial Role of Xanthine Oxidase in CKD Progression Associated with Hypercholesterolemia

by You-Jin Kim, Se-Hyun Oh, Ji-Sun Ahn, Ju-Min Yook, Chan-Duck Kim, Sun-Hee Park, Jang-Hee Cho and Yong-Lim Kim

Int. J. Mol. Sci. 2020, 21(20), 7444; https://doi.org/10.3390/ijms21207444 - 9 Oct 2020

Cited by 15 | Viewed by 3190

Abstract

In the present study, we investigated the effects of xanthine oxidase (XO) inhibition on cholesterol-induced renal dysfunction in chronic kidney disease (CKD) mice, and in low-density lipoprotein (LDL)-treated human kidney proximal tubule epithelial (HK-2) cells. ApoE knockout (KO) mice underwent uninephrectomy to induce [...] Read more.

In the present study, we investigated the effects of xanthine oxidase (XO) inhibition on cholesterol-induced renal dysfunction in chronic kidney disease (CKD) mice, and in low-density lipoprotein (LDL)-treated human kidney proximal tubule epithelial (HK-2) cells. ApoE knockout (KO) mice underwent uninephrectomy to induce CKD, and were fed a normal diet or high-cholesterol (HC) diet along with the XO inhibitor topiroxostat (1 mg/kg/day). HK-2 cells were treated with LDL (200 µg/mL) and topiroxostat (5 µM) or small interfering RNA against xanthine dehydrogenase (siXDH; 20 nM). In uninephrectomized ApoE KO mice, the HC diet increased cholesterol accumulation, oxidative stress, XO activity, and kidney damage, while topiroxostat attenuated the hypercholesterolemia-associated renal dysfunction. The HC diet induced cholesterol accumulation by regulating the expressions of genes involved in cholesterol efflux (Nr1h3 and Abca1) and synthesis (Srebf2 and Hmgcr), which was reversed by topiroxostat. Topiroxostat suppressed the expressions of genes related to hypercholesterolemia-associated inflammation and fibrosis in the unilateral kidney. LDL stimulation evoked changes in the cholesterol metabolism, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and NF-κB pathways in HK-2 cells, which were mitigated by XO inhibition with topiroxostat or siXDH. These findings suggest that XO inhibition exerts renoprotective effects against hypercholesterolemia-associated kidney injury. XO could be a novel therapeutic target for hypercholesterolemia-associated kidney injury in uninephrectomized patients. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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18 pages, 4552 KiB

Open AccessArticle

Protective Effects of Simvastatin on Endotoxin-Induced Acute Kidney Injury through Activation of Tubular Epithelial Cells’ Survival and Hindering Cytochrome C-Mediated Apoptosis

by Lana Nežić, Ranko Škrbić, Ljiljana Amidžić, Radoslav Gajanin, Zoran Milovanović, Eugenie Nepovimova, Kamil Kuča and Vesna Jaćević

Int. J. Mol. Sci. 2020, 21(19), 7236; https://doi.org/10.3390/ijms21197236 - 30 Sep 2020

Cited by 23 | Viewed by 3445

Abstract

Increasing evidence suggests that apoptosis of tubular cells and renal inflammation mainly determine the outcome of sepsis-associated acute kidney injury (AKI). The study aim was to investigate the molecular mechanism involved in the renoprotective effects of simvastatin in endotoxin (lipopolysaccharide, LSP)-induced AKI. A [...] Read more.

Increasing evidence suggests that apoptosis of tubular cells and renal inflammation mainly determine the outcome of sepsis-associated acute kidney injury (AKI). The study aim was to investigate the molecular mechanism involved in the renoprotective effects of simvastatin in endotoxin (lipopolysaccharide, LSP)-induced AKI. A sepsis model was established by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment. The severity of the inflammatory injury was expressed as renal damage scores (RDS). Apoptosis of tubular cells was detected by Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling (TUNEL assay) (apoptotic DNA fragmentation, expressed as an apoptotic index, AI) and immunohistochemical staining for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL and survivin. We found that endotoxin induced severe renal inflammatory injury (RDS = 3.58 ± 0.50), whereas simvastatin dose-dependently prevented structural changes induced by LPS. Furthermore, simvastatin 40 mg/kg most profoundly attenuated tubular apoptosis, determined as a decrease of cytochrome C, caspase-3 expression, and AIs (p < 0.01 vs. LPS). Conversely, simvastatin induced a significant increase of Bcl-XL and survivin, both in the strong inverse correlations with cleaved caspase-3 and cytochrome C. Our study indicates that simvastatin has cytoprotective effects against LPS-induced tubular apoptosis, seemingly mediated by upregulation of cell-survival molecules, such as Bcl-XL and survivin, and inhibition of the mitochondrial cytochrome C and downstream caspase-3 activation. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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14 pages, 2221 KiB

Open AccessArticle

Autophagy Dynamics and Modulation in a Rat Model of Renal Ischemia-Reperfusion Injury

by Jean-Paul Decuypere, Shawn Hutchinson, Diethard Monbaliu, Wim Martinet, Jacques Pirenne and Ina Jochmans

Int. J. Mol. Sci. 2020, 21(19), 7185; https://doi.org/10.3390/ijms21197185 - 29 Sep 2020

Cited by 11 | Viewed by 2623

Abstract

Renal ischemia-reperfusion (IR) injury leading to cell death is a major cause of acute kidney injury, contributing to morbidity and mortality. Autophagy counteracts cell death by removing damaged macromolecules and organelles, making it an interesting anchor point for treatment strategies. However, autophagy is [...] Read more.

Renal ischemia-reperfusion (IR) injury leading to cell death is a major cause of acute kidney injury, contributing to morbidity and mortality. Autophagy counteracts cell death by removing damaged macromolecules and organelles, making it an interesting anchor point for treatment strategies. However, autophagy is also suggested to enhance cell death when the ischemic burden is too strong. To investigate whether the role of autophagy depends on the severity of ischemic stress, we analyzed the dynamics of autophagy and apoptosis in an IR rat model with mild (45 min) or severe (60 min) renal ischemia. Following mild IR, renal injury was associated with reduced autophagy, enhanced mammalian target of rapamycin (mTOR) activity, and apoptosis. Severe IR, on the other hand, was associated with a higher autophagic activity, independent of mTOR, and without affecting apoptosis. Autophagy stimulation by trehalose injected 24 and 48 h prior to onset of severe ischemia did not reduce renal injury markers nor function, but reduced apoptosis and restored tubular dilation 7 days post reperfusion. This suggests that trehalose-dependent autophagy stimulation enhances tissue repair following an IR injury. Our data show that autophagy dynamics are strongly dependent on the severity of IR and that trehalose shows the potential to trigger autophagy-dependent repair processes following renal IR injury. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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17 pages, 6434 KiB

Open AccessArticle

ND-13, a DJ-1-Derived Peptide, Attenuates the Renal Expression of Fibrotic and Inflammatory Markers Associated with Unilateral Ureter Obstruction

by Carmen De Miguel, Abigayle C. Kraus, Mitchell A. Saludes, Prasad Konkalmatt, Almudena Ruiz Domínguez, Laureano D. Asico, Patricia S. Latham, Daniel Offen, Pedro A. Jose and Santiago Cuevas

Int. J. Mol. Sci. 2020, 21(19), 7048; https://doi.org/10.3390/ijms21197048 - 24 Sep 2020

Cited by 9 | Viewed by 3256

Abstract

DJ-1 is a redox-sensitive chaperone with reported antioxidant and anti-inflammatory properties in the kidney. The 20 amino acid (aa) peptide ND-13 consists of 13 highly conserved aas from the DJ-1 sequence and a TAT-derived 7 aa sequence that helps in cell penetration. This [...] Read more.

DJ-1 is a redox-sensitive chaperone with reported antioxidant and anti-inflammatory properties in the kidney. The 20 amino acid (aa) peptide ND-13 consists of 13 highly conserved aas from the DJ-1 sequence and a TAT-derived 7 aa sequence that helps in cell penetration. This study aimed to determine if ND-13 treatment prevents the renal damage and inflammation associated with unilateral ureter obstruction (UUO). Male C57Bl/6 and DJ-1^−/− mice underwent UUO and were treated with ND-13 or vehicle for 14 days. ND-13 attenuated the renal expression of fibrotic markers TGF-β and collagen1a1 (Col1a1) and inflammatory markers TNF-α and IL-6 in C57Bl/6 mice. DJ-1^−/− mice treated with ND-13 presented similar decreased expression of TNF-α, IL-6 and TGF-β. However, in contrast to C57Bl/6 mice, ND-13 failed to prevent renal fibrosis or to ameliorate the expression of Col1a1 in this genotype. Further, UUO led to elevated urinary levels of the proximal tubular injury marker neutrophil gelatinase-associated lipocalin (NGAL) in DJ-1^−/− mice, which were blunted by ND-13. Our results suggest that ND-13 protects against UUO-induced renal injury, inflammation and fibrosis. These are all crucial mechanisms in the pathogenesis of kidney injury. Thus, ND-13 may be a new therapeutic approach to prevent renal diseases. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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16 pages, 4895 KiB

Open AccessArticle

Growth Differentiation Factor 15 Ameliorates Anti-Glomerular Basement Membrane Glomerulonephritis in Mice

by Foteini Moschovaki-Filippidou, Stefanie Steiger, Georg Lorenz, Christoph Schmaderer, Andrea Ribeiro, Ekaterina von Rauchhaupt, Clemens D. Cohen, Hans-Joachim Anders, Maja Lindenmeyer and Maciej Lech

Int. J. Mol. Sci. 2020, 21(19), 6978; https://doi.org/10.3390/ijms21196978 - 23 Sep 2020

Cited by 14 | Viewed by 3378

Abstract

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) cytokine family and an inflammation-associated protein. Here, we investigated the role of GDF15 in murine anti-glomerular basement membrane (GBM) glomerulonephritis. Glomerulonephritis induction in mice induced systemic expression of GDF15. [...] Read more.

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) cytokine family and an inflammation-associated protein. Here, we investigated the role of GDF15 in murine anti-glomerular basement membrane (GBM) glomerulonephritis. Glomerulonephritis induction in mice induced systemic expression of GDF15. Moreover, we demonstrate the protective effects for GDF15, as GDF15-deficient mice exhibited increased proteinuria with an aggravated crescent formation and mesangial expansion in anti-GBM nephritis. Herein, GDF15 was required for the regulation of T-cell chemotactic chemokines in the kidney. In addition, we found the upregulation of the CXCR3 receptor in activated T-cells in GDF15-deficient mice. These data indicate that CXCL10/CXCR3-dependent-signaling promotes the infiltration of T cells into the organ during acute inflammation controlled by GDF15. Together, these results reveal a novel mechanism limiting the migration of lymphocytes to the site of inflammation during glomerulonephritis. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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19 pages, 5199 KiB

Open AccessArticle

NOX1 Inhibition Attenuates Kidney Ischemia-Reperfusion Injury via Inhibition of ROS-Mediated ERK Signaling

by Hee-Yeon Jung, Se-Hyun Oh, Ji-Sun Ahn, Eun-Joo Oh, You-Jin Kim, Chan-Duck Kim, Sun-Hee Park, Yong-Lim Kim and Jang-Hee Cho

Int. J. Mol. Sci. 2020, 21(18), 6911; https://doi.org/10.3390/ijms21186911 - 21 Sep 2020

Cited by 22 | Viewed by 3905

Abstract

The protective effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 1 inhibition against kidney ischemia-reperfusion injury (IRI) remain uncertain. The bilateral kidney pedicles of C57BL/6 mice were clamped for 30 min to induce IRI. Madin–Darby Canine Kidney (MDCK) cells were incubated with [...] Read more.

The protective effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 1 inhibition against kidney ischemia-reperfusion injury (IRI) remain uncertain. The bilateral kidney pedicles of C57BL/6 mice were clamped for 30 min to induce IRI. Madin–Darby Canine Kidney (MDCK) cells were incubated with H₂O₂ (1.4 mM) for 1 h to induce oxidative stress. ML171, a selective NOX1 inhibitor, and siRNA against NOX1 were treated to inhibit NOX1. NOX expression, oxidative stress, apoptosis assay, and mitogen-activated protein kinase (MAPK) pathway were evaluated. The kidney function deteriorated and the production of reactive oxygen species (ROS), including intracellular H₂O₂ production, increased due to IRI, whereas IRI-mediated kidney dysfunction and ROS generation were significantly attenuated by ML171. H₂O₂ evoked the changes in oxidative stress enzymes such as SOD2 and GPX in MDCK cells, which was mitigated by ML171. Treatment with ML171 and transfection with siRNA against NOX1 decreased the upregulation of NOX1 and NOX4 induced by H₂O₂ in MDCK cells. ML171 decreased caspase-3 activity, the Bcl-2/Bax ratio, and TUNEL-positive tubule cells in IRI mice and H₂O₂-treated MDCK cells. Among the MAPK pathways, ML171 affected ERK signaling by ERK phosphorylation in kidney tissues and tubular cells. NOX1-selective inhibition attenuated kidney IRI via inhibition of ROS-mediated ERK signaling. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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13 pages, 13934 KiB

Open AccessArticle

Cyclophilin A Promotes Inflammation in Acute Kidney Injury but Not in Renal Fibrosis

by Khai Gene Leong, Elyce Ozols, John Kanellis, David J. Nikolic-Paterson and Frank Y. Ma

Int. J. Mol. Sci. 2020, 21(10), 3667; https://doi.org/10.3390/ijms21103667 - 22 May 2020

Cited by 18 | Viewed by 3641

Abstract

Cyclophilin A (CypA) is a highly abundant protein in the cytoplasm of most mammalian cells. Beyond its homeostatic role in protein folding, CypA is a Damage-Associated Molecular Pattern which can promote inflammation during tissue injury. However, the role of CypA in kidney disease [...] Read more.

Cyclophilin A (CypA) is a highly abundant protein in the cytoplasm of most mammalian cells. Beyond its homeostatic role in protein folding, CypA is a Damage-Associated Molecular Pattern which can promote inflammation during tissue injury. However, the role of CypA in kidney disease is largely unknown. This study investigates the contribution of CypA in two different types of kidney injury: acute tubular necrosis and progressive interstitial fibrosis. CypA (Ppia) gene deficient and wild type (WT) littermate controls underwent bilateral renal ischaemia/reperfusion injury (IRI) and were killed 24 h later or underwent left unilateral ureteric obstruction (UUO) and were killed 7 days later. In the IRI model, CypA^−/− mice showed substantial protection against the loss of renal function and from tubular cell damage and death. This was attributed to a significant reduction in neutrophil and macrophage infiltration since CypA^−/− tubular cells were not protected from oxidant-induced cell death in vitro. In the UUO model, CypA^−/− mice were not protected from leukocyte infiltration or renal interstitial fibrosis. In conclusion, CypA promotes inflammation and acute kidney injury in renal IRI, but does not contribute to inflammation or interstitial fibrosis in a model of progressive kidney fibrosis. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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16 pages, 3505 KiB

Open AccessArticle

Cilastatin Preconditioning Attenuates Renal Ischemia-Reperfusion Injury via Hypoxia Inducible Factor-1α Activation

by Yu Ah Hong, So Young Jung, Keum Jin Yang, Dai Sig Im, Kyung Hwan Jeong, Cheol Whee Park and Hyeon Seok Hwang

Int. J. Mol. Sci. 2020, 21(10), 3583; https://doi.org/10.3390/ijms21103583 - 19 May 2020

Cited by 12 | Viewed by 3609

Abstract

Cilastatin is a specific inhibitor of renal dehydrodipeptidase-1. We investigated whether cilastatin preconditioning attenuates renal ischemia-reperfusion (IR) injury via hypoxia inducible factor-1α (HIF-1α) activation. Human proximal tubular cell line (HK-2) was exposed to ischemia, and male C57BL/6 mice were subjected to bilateral kidney [...] Read more.

Cilastatin is a specific inhibitor of renal dehydrodipeptidase-1. We investigated whether cilastatin preconditioning attenuates renal ischemia-reperfusion (IR) injury via hypoxia inducible factor-1α (HIF-1α) activation. Human proximal tubular cell line (HK-2) was exposed to ischemia, and male C57BL/6 mice were subjected to bilateral kidney ischemia and reperfusion. The effects of cilastatin preconditioning were investigated both in vitro and in vivo. In HK-2 cells, cilastatin upregulated HIF-1α expression in a time- and dose-dependent manner. Cilastatin enhanced HIF-1α translation via the phosphorylation of Akt and mTOR was followed by the upregulation of erythropoietin (EPO) and vascular endothelial growth factor (VEGF). Cilastatin did not affect the expressions of PHD and VHL. However, HIF-1α ubiquitination was significantly decreased after cilastatin treatment. Cilastatin prevented the IR-induced cell death. These cilastatin effects were reversed by co-treatment of HIF-1α inhibitor or HIF-1α small interfering RNA. Similarly, HIF-1α expression and its upstream and downstream signaling were significantly enhanced in cilastatin-treated kidney. In mouse kidney with IR injury, cilastatin treatment decreased HIF-1α ubiquitination independent of PHD and VHL expression. Serum creatinine level and tubular necrosis, and apoptosis were reduced in cilastatin-treated kidney with IR injury, and co-treatment of cilastatin with an HIF-1α inhibitor reversed these effects. Thus, cilastatin preconditioning attenuated renal IR injury via HIF-1α activation. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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17 pages, 4181 KiB

Open AccessArticle

Macrophage-Secreted Lipocalin-2 Promotes Regeneration of Injured Primary Murine Renal Tubular Epithelial Cells

by Anja Urbschat, Anne-Kathrin Thiemens, Christina Mertens, Claudia Rehwald, Julia K. Meier, Patrick C. Baer and Michaela Jung

Int. J. Mol. Sci. 2020, 21(6), 2038; https://doi.org/10.3390/ijms21062038 - 16 Mar 2020

Cited by 19 | Viewed by 4260

Abstract

Lipocalin-2 (Lcn-2) is rapidly upregulated in macrophages after renal tubular injury and acts as renoprotective and pro-regenerative agent. Lcn-2 possesses the ability to bind and transport iron with high affinity. Therefore, the present study focuses on the decisive role of the Lcn-2 iron-load [...] Read more.

Lipocalin-2 (Lcn-2) is rapidly upregulated in macrophages after renal tubular injury and acts as renoprotective and pro-regenerative agent. Lcn-2 possesses the ability to bind and transport iron with high affinity. Therefore, the present study focuses on the decisive role of the Lcn-2 iron-load for its pro-regenerative function. Primary mouse tubular epithelial cells were isolated from kidney tissue of wildtype mice and incubated with 5 µM Cisplatin for 24 h to induce injury. Bone marrow-derived macrophages of wildtype and Lcn-2^−/− mice were isolated and polarized with IL-10 towards an anti-inflammatory, iron-release phenotype. Their supernatants as well as recombinant iron-loaded holo-Lcn-2 was used for stimulation of Cisplatin-injured tubular epithelial cells. Incubation of tubular epithelial cells with wildtype supernatants resulted in less damage and induced cellular proliferation, whereas in absence of Lcn-2 no protective effect was observed. Epithelial integrity as well as cellular proliferation showed a clear protection upon rescue experiments applying holo-Lcn-2. Notably, we detected a positive correlation between total iron amounts in tubular epithelial cells and cellular proliferation, which, in turn, reinforced the assumed link between availability of Lcn-2-bound iron and recovery. We hypothesize that macrophage-released Lcn-2-bound iron is provided to tubular epithelial cells during toxic cell damage, whereby injury is limited and recovery is favored. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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Review

Jump to: Editorial, Research

16 pages, 599 KiB

Open AccessReview

Emerging Modes of Treatment of IgA Nephropathy

by Dita Maixnerova and Vladimir Tesar

Int. J. Mol. Sci. 2020, 21(23), 9064; https://doi.org/10.3390/ijms21239064 - 28 Nov 2020

Cited by 23 | Viewed by 5470

Abstract

IgA nephropathy is the most common primary glomerulonephritis with potentially serious outcome leading to end stage renal disease in 30 to 50% of patients within 20 to 30 years. Renal biopsy, which might be associated with risks of complications (bleeding and others), still [...] Read more.

IgA nephropathy is the most common primary glomerulonephritis with potentially serious outcome leading to end stage renal disease in 30 to 50% of patients within 20 to 30 years. Renal biopsy, which might be associated with risks of complications (bleeding and others), still remains the only reliable diagnostic tool for IgA nephropathy. Therefore, the search for non-invasive diagnostic and prognostic markers for detection of subclinical types of IgA nephropathy, evaluation of disease activity, and assessment of treatment effectiveness, is of utmost importance. In this review, we summarize treatment options for patients with IgA nephropathy including the drugs currently under evaluation in randomized control trials. An early initiation of immunosupressive regimens in patients with IgA nephropathy at risk of progression should result in the slowing down of the progression of renal function to end stage renal disease. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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27 pages, 3191 KiB

Open AccessReview

Toll-Like Receptor as a Potential Biomarker in Renal Diseases

by Sebastian Mertowski, Paulina Lipa, Izabela Morawska, Paulina Niedźwiedzka-Rystwej, Dominika Bębnowska, Rafał Hrynkiewicz, Ewelina Grywalska, Jacek Roliński and Wojciech Załuska

Int. J. Mol. Sci. 2020, 21(18), 6712; https://doi.org/10.3390/ijms21186712 - 13 Sep 2020

Cited by 14 | Viewed by 5240

Abstract

One of the major challenges faced by modern nephrology is the identification of biomarkers associated with histopathological patterns or defined pathogenic mechanisms that may assist in the non-invasive diagnosis of kidney disease, particularly glomerulopathy. The identification of such molecules may allow prognostic subgroups [...] Read more.

One of the major challenges faced by modern nephrology is the identification of biomarkers associated with histopathological patterns or defined pathogenic mechanisms that may assist in the non-invasive diagnosis of kidney disease, particularly glomerulopathy. The identification of such molecules may allow prognostic subgroups to be established based on the type of disease, thereby predicting response to treatment or disease relapse. Advances in understanding the pathogenesis of diseases, such as membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, IgA (immunoglobulin A) nephropathy, and diabetic nephropathy, along with the progressive development and standardization of plasma and urine proteomics techniques, have facilitated the identification of an increasing number of molecules that may be useful for these purposes. The growing number of studies on the role of TLR (toll-like receptor) receptors in the pathogenesis of kidney disease forces contemporary researchers to reflect on these molecules, which may soon join the group of renal biomarkers and become a helpful tool in the diagnosis of glomerulopathy. In this article, we conducted a thorough review of the literature on the role of TLRs in the pathogenesis of glomerulopathy. The role of TLR receptors as potential marker molecules for the development of neoplastic diseases is emphasized more and more often, as prognostic factors in diseases on several epidemiological backgrounds. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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10 pages, 219 KiB

Open AccessReview

The Role of Endocan in Selected Kidney Diseases

by Magdalena Nalewajska, Klaudia Gurazda, Małgorzata Marchelek-Myśliwiec, Andrzej Pawlik and Violetta Dziedziejko

Int. J. Mol. Sci. 2020, 21(17), 6119; https://doi.org/10.3390/ijms21176119 - 25 Aug 2020

Cited by 12 | Viewed by 2604

Abstract

Endocan, previously referred to as an endothelial-cell-specific molecule-1 (ESM-1) is a member of a proteoglycan family that is secreted by vascular endothelial cells of different organs, mainly lungs and kidneys. It is assumed to participate in endothelial activation and the triggering of inflammatory [...] Read more.

Endocan, previously referred to as an endothelial-cell-specific molecule-1 (ESM-1) is a member of a proteoglycan family that is secreted by vascular endothelial cells of different organs, mainly lungs and kidneys. It is assumed to participate in endothelial activation and the triggering of inflammatory reactions, especially in microvasculatures. Thanks to its solubility in human fluids, i.e., urine and blood plasma, its stability and its low concentrations in physiological conditions, endocan has been proposed as an easily available, non-invasive biomarker for identifying and predicting the course of many diseases. Recently, endocan has been studied in relation to kidney diseases. In general, endocan levels have been linked to worse clinical outcomes of renal dysfunction; however, results are conflicting and require further evaluation. In this review, authors summarize available knowledge regarding the role of endocan in pathogenesis and progression of selected kidney diseases. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

11 pages, 847 KiB

Open AccessReview

Podocytes—The Most Vulnerable Renal Cells in Preeclampsia

by Ewa Kwiatkowska, Katarzyna Stefańska, Maciej Zieliński, Justyna Sakowska, Martyna Jankowiak, Piotr Trzonkowski, Natalia Marek-Trzonkowska and Sebastian Kwiatkowski

Int. J. Mol. Sci. 2020, 21(14), 5051; https://doi.org/10.3390/ijms21145051 - 17 Jul 2020

Cited by 19 | Viewed by 4063

Abstract

Preeclampsia (PE) is a disorder that affects 3–5% of normal pregnancies. It was believed for a long time that the kidney, similarly to all vessels in the whole system, only sustained endothelial damage. The current knowledge gives rise to a presumption that the [...] Read more.

Preeclampsia (PE) is a disorder that affects 3–5% of normal pregnancies. It was believed for a long time that the kidney, similarly to all vessels in the whole system, only sustained endothelial damage. The current knowledge gives rise to a presumption that the main role in the development of proteinuria is played by damage to the podocytes and their slit diaphragm. The podocyte damage mechanism in preeclampsia is connected to free VEGF and nitric oxide (NO) deficiency, and an increased concentration of endothelin-1 and oxidative stress. From national cohort studies, we know that women who had preeclampsia in at least one pregnancy carried five times the risk of developing end-stage renal disease (ESRD) when compared to women with physiological pregnancies. The focal segmental glomerulosclerosis (FSGS) is the dominant histopathological lesion in women with a history of PE. The kidney’s podocytes are not subject to replacement or proliferation. Podocyte depletion exceeding 20% resulted in FSGS, which is a reason for the later development of ESRD. In this review, we present the mechanism of kidney (especially podocytes) injury in preeclampsia. We try to explain how this damage affects further changes in the morphology and function of the kidneys after pregnancy. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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25 pages, 430 KiB

Open AccessReview

The Influence of Inflammation on Anemia in CKD Patients

by Anna Gluba-Brzózka, Beata Franczyk, Robert Olszewski and Jacek Rysz

Int. J. Mol. Sci. 2020, 21(3), 725; https://doi.org/10.3390/ijms21030725 - 22 Jan 2020

Cited by 80 | Viewed by 10808

Abstract

Anemia is frequently observed in the course of chronic kidney disease (CKD) and it is associated with diminishing the quality of a patient’s life. It also enhances morbidity and mortality and hastens the CKD progression rate. Patients with CKD frequently suffer from a [...] Read more.

Anemia is frequently observed in the course of chronic kidney disease (CKD) and it is associated with diminishing the quality of a patient’s life. It also enhances morbidity and mortality and hastens the CKD progression rate. Patients with CKD frequently suffer from a chronic inflammatory state which is related to a vast range of underlying factors. The results of studies have demonstrated that persistent inflammation may contribute to the variability in Hb levels and hyporesponsiveness to erythropoietin stimulating agents (ESA), which are frequently observed in CKD patients. The understanding of the impact of inflammatory cytokines on erythropoietin production and hepcidin synthesis will enable one to unravel the net of interactions of multiple factors involved in the pathogenesis of the anemia of chronic disease. It seems that anti-cytokine and anti-oxidative treatment strategies may be the future of pharmacological interventions aiming at the treatment of inflammation-associated hyporesponsiveness to ESA. The discovery of new therapeutic approaches towards the treatment of anemia in CKD patients has become highly awaited. The treatment of anemia with erythropoietin (EPO) was associated with great benefits for some patients but not all. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration 2020)

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