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

Deadline for manuscript submissions: closed (17 March 2019) | Viewed by 48219

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Dr. Keiko Hosohata

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Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki 569-1094, Japan
Interests: inflammation; reactive oxygen species; renal physiology; blood pressure regulation; biomarker; clinical pharmacology; toxicology
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Dear colleagues,

"Kindey injury" occurs at various stages of kidney disease. Renal fibrosis from kidney injury is a common pathway for the progression to chronic kidney disease (CKD). Despite the significant burden of CKD, specific therapies to prevent its incidence and progression remain limited. Therefore, novel therapies to prevent the decline of kidney function are needed.

This Special Issue of the International Journal of Molecular Sciences will focus on "Kidney Injury: From Molecular Basis to Therapies". It will include papers investigating the pathological mechanisms of CKD and experimental and clinical studies examining potential treatments to attenuate kidney dysfunction. In addition, works exploring the progression from acute kidney injury to CKD are welcome.

Dr. Keiko Hosohata
Guest Editor

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Kidney Injury: From Molecular Basis to Therapies 2.0 in International Journal of Molecular Sciences (18 articles)

Published Papers (9 papers)

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Research

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12 pages, 3512 KiB

Open AccessArticle

Involvement of Vanin-1 in Ameliorating Effect of Oxidative Renal Tubular Injury in Dahl-Salt Sensitive Rats

by Keiko Hosohata, Denan Jin, Shinji Takai and Kazunori Iwanaga

Int. J. Mol. Sci. 2019, 20(18), 4481; https://doi.org/10.3390/ijms20184481 - 11 Sep 2019

Cited by 14 | Viewed by 3120

Abstract

In salt-sensitive hypertension, reactive oxygen species (ROS) play a major role in the progression of renal disease partly through the activation of the mineralocorticoid receptor (MR). We have previously demonstrated that urinary vanin-1 is an early biomarker of oxidative renal tubular injury. However, it remains unknown whether urinary vanin-1 might reflect the treatment effect. The objective of this study was to clarify the treatment effect for renal tubular damage in Dahl salt-sensitive (DS) rats. DS rats (six weeks old) were given one of the following for four weeks: high-salt diet (8% NaCl), high-salt diet plus a superoxide dismutase mimetic, tempol (3 mmol/L in drinking water), high-salt diet plus eplerenone (100 mg/kg/day), and normal-salt diet (0.3% NaCl). After four-week treatment, blood pressure was measured and kidney tissues were evaluated. ROS were assessed by measurements of malondialdehyde and by immunostaining for 4-hydroxy-2-nonenal. A high-salt intake for four weeks caused ROS and histological renal tubular damages in DS rats, both of which were suppressed by tempol and eplerenone. Proteinuria and urinary N-acetyl-β-D-glucosaminidase exhibited a significant decrease in DS rats receiving a high-salt diet plus eplerenone, but not tempol. In contrast, urinary vanin-1 significantly decreased in DS rats receiving a high-salt diet plus eplerenone as well as tempol. Consistent with these findings, immunohistochemical analysis revealed that vanin-1 was localized in the renal proximal tubules but not the glomeruli in DS rats receiving a high-salt diet, with the strength attenuated by tempol or eplerenone treatment. In conclusion, these results suggest that urinary vanin-1 is a potentially sensitive biomarker for ameliorating renal tubular damage in salt-sensitive hypertension. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies)

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15 pages, 3283 KiB

Open AccessArticle

Cadmium Complexed with β2-Microglubulin, Albumin and Lipocalin-2 rather than Metallothionein Cause Megalin:Cubilin Dependent Toxicity of the Renal Proximal Tubule

by Johannes Fels, Bettina Scharner, Ralf Zarbock, Itzel Pamela Zavala Guevara, Wing-Kee Lee, Olivier C. Barbier and Frank Thévenod

Int. J. Mol. Sci. 2019, 20(10), 2379; https://doi.org/10.3390/ijms20102379 - 14 May 2019

Cited by 32 | Viewed by 4532

Abstract

Cadmium (Cd²⁺) in the environment is a significant health hazard. Chronic low Cd²⁺ exposure mainly results from food and tobacco smoking and causes kidney damage, predominantly in the proximal tubule. Blood Cd²⁺ binds to thiol-containing high (e.g., albumin, transferrin) and low molecular weight proteins (e.g., the high-affinity metal-binding protein metallothionein, β2-microglobulin, α1-microglobulin and lipocalin-2). These plasma proteins reach the glomerular filtrate and are endocytosed at the proximal tubule via the multiligand receptor complex megalin:cubilin. The current dogma of chronic Cd²⁺ nephrotoxicity claims that Cd²⁺-metallothionein endocytosed via megalin:cubilin causes renal damage. However, a thorough study of the literature strongly argues for revision of this model for various reasons, mainly: (i) It relied on studies with unusually high Cd²⁺-metallothionein concentrations; (ii) the K_D of megalin for metallothionein is ~10⁵-times higher than (Cd²⁺)-metallothionein plasma concentrations. Here we investigated the uptake and toxicity of ultrafiltrated Cd²⁺-binding protein ligands that are endocytosed via megalin:cubilin in the proximal tubule. Metallothionein, β2-microglobulin, α1-microglobulin, lipocalin-2, albumin and transferrin were investigated, both as apo- and Cd²⁺-protein complexes, in a rat proximal tubule cell line (WKPT-0293 Cl.2) expressing megalin:cubilin at low passage, but is lost at high passage. Uptake was determined by fluorescence microscopy and toxicity by MTT cell viability assay. Apo-proteins in low and high passage cells as well as Cd²⁺-protein complexes in megalin:cubilin deficient high passage cells did not affect cell viability. The data prove Cd²⁺-metallothionein is not toxic, even at >100-fold physiological metallothionein concentrations in the primary filtrate. Rather, Cd²⁺-β2-microglobulin, Cd²⁺-albumin and Cd²⁺-lipocalin-2 at concentrations present in the primary filtrate are taken up by low passage proximal tubule cells and cause toxicity. They are therefore likely candidates of Cd²⁺-protein complexes damaging the proximal tubule via megalin:cubilin at concentrations found in the ultrafiltrate. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies)

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18 pages, 2926 KiB

Open AccessArticle

Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease

by Juliana Isa Beraldo, Acaris Benetti, Flávio Araújo Borges-Júnior, Daniel F. Arruda-Junior, Flavia Letícia Martins, Leonardo Jensen, Rafael Dariolli, Maria Heloisa Shimizu, Antonio C. Seguro, Weverton M. Luchi and Adriana C. C. Girardi

Int. J. Mol. Sci. 2019, 20(8), 1940; https://doi.org/10.3390/ijms20081940 - 20 Apr 2019

Cited by 26 | Viewed by 4092

Abstract

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies)

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15 pages, 6713 KiB

Open AccessArticle

Inhibition of p300/CBP-Associated Factor Attenuates Renal Tubulointerstitial Fibrosis through Modulation of NF-kB and Nrf2

by Sungjin Chung, Soojeong Kim, Mina Son, Minyoung Kim, Eun Sil Koh, Seok Joon Shin, Cheol Whee Park and Ho-Shik Kim

Int. J. Mol. Sci. 2019, 20(7), 1554; https://doi.org/10.3390/ijms20071554 - 28 Mar 2019

Cited by 48 | Viewed by 5087

Abstract

p300/CBP-associated factor (PCAF), a histone acetyltransferase, is involved in many cellular processes such as differentiation, proliferation, apoptosis, and reaction to cell damage by modulating the activities of several genes and proteins through the acetylation of either the histones or transcription factors. Here, we examined a pathogenic role of PCAF and its potential as a novel therapeutic target in the progression of renal tubulointerstitial fibrosis induced by non-diabetic unilateral ureteral obstruction (UUO) in male C57BL/6 mice. Administration of garcinol, a PCAF inhibitor, reversed a UUO-induced increase in the renal expression of total PCAF and histone 3 lysine 9 acetylation and reduced positive areas of trichrome and α-smooth muscle actin and collagen content. Treatment with garcinol also decreased mRNA levels of transforming growth factor-β, matrix metalloproteinase (MMP)-2, MMP-9, and fibronectin. Furthermore, garcinol suppressed nuclear factor-κB (NF-κB) and pro-inflammatory cytokines such as tumor necrosis factor-α and IL-6, whereas it preserved the nuclear expression of nuclear factor erythroid-derived 2-like factor 2 (Nrf2) and levels of Nrf2-dependent antioxidants including heme oxygense-1, catalase, superoxide dismutase 1, and NAD(P)H:quinone oxidoreductase 1. These results suggest that the inhibition of inordinately enhanced PCAF could mitigate renal fibrosis by redressing aberrant balance between inflammatory signaling and antioxidant response through the modulation of NF-κB and Nrf2. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies)

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14 pages, 2192 KiB

Open AccessArticle

A Novel Biomarker for Acute Kidney Injury, Vanin-1, for Obstructive Nephropathy: A Prospective Cohort Pilot Study

by Satoshi Washino, Keiko Hosohata, Masashi Oshima, Tomohisa Okochi, Tsuzumi Konishi, Yuhki Nakamura, Kimitoshi Saito and Tomoaki Miyagawa

Int. J. Mol. Sci. 2019, 20(4), 899; https://doi.org/10.3390/ijms20040899 - 19 Feb 2019

Cited by 24 | Viewed by 4167

Abstract

Background: Vanin-1 is a novel acute kidney injury (AKI) biomarker that has not been clinically investigated as a biomarker for obstructive nephropathy. This study investigated the diagnostic value of vanin-1 as a biomarker for adult obstructive nephropathy by comparing it to existing AKI biomarkers. Methods: A total of 49 patients, 21 controls, and 28 hydronephrosis (HN) cases were assessed. AKI biomarkers in bladder (BL) urine and renal pelvic (RP) urine in the HN group were compared to each BL marker in the control group. In a subgroup of cases receiving interventions for obstructive nephropathy, the BL values of each biomarker were assessed after the intervention. Results: RP vanin-1 levels were significantly higher while BL vanin-1 levels were marginally higher in the HN group than in the control group. The area under the receiver operating characteristics curve values for RP and BL vanin-1 were 0.9778 and 0.6386, respectively. In multivariate analyses, BL vanin-1 and N-acetyl-β-D-glucosaminidase (NAG), but not kidney injury molecule-1 (KIM-1) or neutrophil gelatinase-associated lipocalin (NGAL), were independent factors for predicting the presence of HN. In cases receiving interventions, vanin-1 decreased significantly from 1 week after the intervention in cases of moderate to severe obstructive nephropathy compared to RP values at baseline. Conclusion: Urinary vanin-1 is a useful biomarker to detect and monitor the clinical course of obstructive nephropathy. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies)

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13 pages, 9705 KiB

Open AccessArticle

Renoprotective Effect of the Histone Deacetylase Inhibitor CG200745 in DOCA-Salt Hypertensive Rats

by Eun Hui Bae, In Jin Kim, Ji Hong Song, Hong Sang Choi, Chang Seong Kim, Gwang Hyeon Eom, Inkyeom Kim, Hyunju Cha, Joong Myung Cho, Seong Kwon Ma and Soo Wan Kim

Int. J. Mol. Sci. 2019, 20(3), 508; https://doi.org/10.3390/ijms20030508 - 25 Jan 2019

Cited by 8 | Viewed by 4749

Abstract

The novel histone deacetylase inhibitor CG200745 was initially developed to treat various hematological and solid cancers. We investigated the molecular mechanisms associated with the renoprotective effects of CG200745 using deoxycorticosterone acetate (DOCA)-salt hypertensive (DSH) rats. DOCA strips (200 mg/kg) were implanted into rats one week after unilateral nephrectomy. Two weeks after DOCA implantation, DSH rats were randomly divided into two groups that received either physiological saline or CG200745 (5 mg/kg/day) for another two weeks. The extent of glomerulosclerosis and tubulointerstitial fibrosis was determined by Masson’s trichrome staining. The renal expression of fibrosis and inflammatory markers was detected by semiquantitative immunoblotting, a polymerase chain reaction, and immunohistochemistry. Pathological signs such as glomerulosclerosis, tubulointerstitial fibrosis, increased systolic blood pressure, decreased creatinine clearance, and increased albumin-to-creatinine ratios in DSH rats were alleviated by CG200745 treatment compared to those manifestations in positive control animals. Furthermore, this treatment counteracted the increased expression of αSMA, TGF-β1, and Bax, and the decreased expression of Bcl-2 in the kidneys of DSH rats. It also attenuated the increase in the number of apoptotic cells in DSH rats. Thus, CG200745 can effectively prevent the progression of renal injury in DSH rats by exerting anti-inflammatory, anti-fibrotic, and anti-apoptotic effects. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies)

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12 pages, 1336 KiB

Open AccessArticle

Association of HbA_1C Variability and Renal Progression in Patients with Type 2 Diabetes with Chronic Kidney Disease Stages 3–4

by Mei-Yueh Lee, Jiun-Chi Huang, Szu-Chia Chen, Hsin-Ying Clair Chiou and Pei-Yu Wu

Int. J. Mol. Sci. 2018, 19(12), 4116; https://doi.org/10.3390/ijms19124116 - 18 Dec 2018

Cited by 28 | Viewed by 5443

Abstract

Little is known about the predictive value of glycosylated hemoglobin (HbA_1C) variability in patients with advanced chronic kidney disease (CKD). The aim of this study was to investigate whether HbA_1C variability is associated with progression to end-stage renal disease in diabetic patients with stages 3–5 CKD, and whether different stages of CKD affect these associations. Three hundred and eighty-eight patients with diabetes and stages 3–5 CKD were enrolled in this longitudinal study. Intra-individual HbA_1C variability was defined as the standard deviation (SD) of HbA_1C, and the renal endpoint was defined as commencing dialysis. The results indicated that, during a median follow-up period of 3.5 years, 108 patients started dialysis. Adjusted Cox analysis showed an association between the highest tertile of HbA_1C SD (tertile 3 vs. tertile 1) and a lower risk of the renal endpoint (hazard ratio = 0.175; 95% confidence interval = 0.059–0.518; p = 0.002) in the patients with an HbA_1C level ≥ 7% and stages 3–4 CKD, but not in stage 5 CKD. Further subgroup analysis showed that the highest two tertiles of HbA_1C SD were associated with a lower risk of the renal endpoint in the group with a decreasing trend of HbA_1C. Our results demonstrated that greater HbA_1C variability and a decreasing trend of HbA_1C, which may be related to intensive diabetes control, was associated with a lower risk of progression to dialysis in the patients with stages 3–4 CKD and poor glycemic control (HbA1c ≥ 7%). Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies)

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9 pages, 4406 KiB

Open AccessArticle

Vanin-1 in Renal Pelvic Urine Reflects Kidney Injury in a Rat Model of Hydronephrosis

by Keiko Hosohata, Denan Jin, Shinji Takai and Kazunori Iwanaga

Int. J. Mol. Sci. 2018, 19(10), 3186; https://doi.org/10.3390/ijms19103186 - 16 Oct 2018

Cited by 17 | Viewed by 4473

Abstract

Urinary tract obstruction and the subsequent development of hydronephrosis can cause kidney injuries, which results in chronic kidney disease. Although it is important to detect kidney injuries at an early stage, new biomarkers of hydronephrosis have not been identified. In this study, we examined whether vanin-1 could be a potential biomarker for hydronephrosis. Male Sprague-Dawley rats were subjected to unilateral ureteral obstruction (UUO). On day 7 after UUO, when the histopathological renal tubular injuries became obvious, the vanin-1 level in the renal pelvic urine was significantly higher than that in voided urine from sham-operated rats. Furthermore, vanin-1 remained at the same level until day 14. There was no significant difference in the serum vanin-1 level between sham-operated rats and rats with UUO. In the kidney tissue, the mRNA and protein expressions of vanin-1 significantly decreased, whereas there was increased expression of transforming growth factor (TGF)-β1 and Snail-1, which plays a pivotal role in the pathogenesis of renal fibrosis via epithelial-to-mesenchymal transition (EMT). These results suggest that vanin-1 in the renal pelvic urine is released from the renal tubular cells of UUO rats and reflects renal tubular injuries at an early stage. Urinary vanin-1 may serve as a candidate biomarker of renal tubular injury due to hydronephrosis. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies)

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Review

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26 pages, 643 KiB

Open AccessReview

Stem Cell Therapies in Kidney Diseases: Progress and Challenges

by Cinzia Rota, Marina Morigi and Barbara Imberti

Int. J. Mol. Sci. 2019, 20(11), 2790; https://doi.org/10.3390/ijms20112790 - 7 Jun 2019

Cited by 55 | Viewed by 11749

Abstract

The prevalence of renal diseases is emerging as a public health problem. Despite major progress in supportive therapy, mortality rates among patients remain high. In an attempt to find innovative treatments to stimulate kidney regeneration, stem cell-based technology has been proposed as a potentially promising strategy. Here, we summarise the renoprotective potential of pluripotent and adult stem cell therapy in experimental models of acute and chronic kidney injury and we explore the different mechanisms at the basis of stem cell-induced kidney regeneration. Specifically, cell engraftment, incorporation into renal structures, or paracrine activities of embryonic or induced pluripotent stem cells as well as mesenchymal stem cells and renal precursors are analysed. We also discuss the relevance of stem cell secretome-derived bioproducts, including soluble factors and extracellular vesicles, and the option of using them as cell-free therapy to induce reparative processes. The translation of the experimental results into clinical trials is also addressed, highlighting the safety and feasibility of stem cell treatments in patients with kidney injury. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies)

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