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12 pages, 1763 KiB

Open AccessArticle

The Time-Feature of Uric Acid Excretion in Hyperuricemia Mice Induced by Potassium Oxonate and Adenine

by Shaoshi Wen, Dan Wang, Haiyang Yu, Mengyang Liu, Qian Chen, Ruixia Bao, Lin Liu, Yi Zhang and Tao Wang

Int. J. Mol. Sci. 2020, 21(15), 5178; https://doi.org/10.3390/ijms21155178 - 22 Jul 2020

Cited by 41 | Viewed by 5494

Abstract

Hyperuricemia is an important risk factor of chronic kidney disease, metabolic syndrome and cardiovascular disease. We aimed to assess the time-feature relationship of hyperuricemia mouse model on uric acid excretion and renal function. A hyperuricemia mouse model was established by potassium oxonate (PO) [...] Read more.

Hyperuricemia is an important risk factor of chronic kidney disease, metabolic syndrome and cardiovascular disease. We aimed to assess the time-feature relationship of hyperuricemia mouse model on uric acid excretion and renal function. A hyperuricemia mouse model was established by potassium oxonate (PO) and adenine for 21 days. Ultra Performance Liquid Chromatography was used to determine plasma uric acid level. Hematoxylin-eosin staining was applied to observe kidney pathological changes, and Western blot was used to detect renal urate transporters’ expression. In hyperuricemia mice, plasma uric acid level increased significantly from the 3rd day, and tended to be stable from the 7th day, and the clearance rate of uric acid decreased greatly from the 3rd day. Further study found that the renal organ of hyperuricemia mice showed slight damage from the 3rd day, and significantly deteriorated renal function from the 10th day. In addition, the expression levels of GLUT9 and URAT1 were upregulated from the 3rd day, while ABCG2 and OAT1 were downregulated from the 3rd day, and NPT1 were downregulated from the 7th day in hyperuricemia mice kidney. This paper presents a method suitable for experimental hyperuricemia mouse model, and shows the time-feature of each index in a hyperuricemia mice model. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies 2.0)

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16 pages, 3359 KiB

Open AccessArticle

Reproducible Large-Scale Isolation of Exosomes from Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells and Their Application in Acute Kidney Injury

by Jun Ho Lee, Dae Hyun Ha, Hyeon-kyu Go, Jinkwon Youn, Hyun-keun Kim, Richard C. Jin, Randy B. Miller, Do-hyung Kim, Byong Seung Cho and Yong Weon Yi

Int. J. Mol. Sci. 2020, 21(13), 4774; https://doi.org/10.3390/ijms21134774 - 5 Jul 2020

Cited by 77 | Viewed by 8029

Abstract

Acute kidney injury (AKI) is a fatal medical episode caused by sudden kidney damage or failure, leading to the death of patients within a few hours or days. Previous studies demonstrated that exosomes derived from various mesenchymal stem/stromal cells (MSC-exosomes) have positive effects [...] Read more.

Acute kidney injury (AKI) is a fatal medical episode caused by sudden kidney damage or failure, leading to the death of patients within a few hours or days. Previous studies demonstrated that exosomes derived from various mesenchymal stem/stromal cells (MSC-exosomes) have positive effects on renal injuries in multiple experimental animal models of kidney diseases including AKI. However, the mass production of exosomes is a challenge not only in preclinical studies with large animals but also for successful clinical applications. In this respect, tangential flow filtration (TFF) is suitable for good manufacturing practice (GMP)-compliant large-scale production of high-quality exosomes. Until now, no studies have been reported on the use of TFF, but rather ultracentrifugation has been almost exclusively used, to isolate exosomes for AKI therapeutic application in preclinical studies. Here, we demonstrated the reproducible large-scale production of exosomes derived from adipose tissue-derived MSC (ASC-exosomes) using TFF and the lifesaving effect of the ASC-exosomes in a lethal model of cisplatin-induced rat AKI. Our results suggest the possibility of large-scale stable production of ASC-exosomes without loss of function and their successful application in life-threatening diseases. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies 2.0)

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17 pages, 4036 KiB

Open AccessArticle

IGF-1 Deficiency Rescue and Intracellular Calcium Blockade Improves Survival and Corresponding Mechanisms in a Mouse Model of Acute Kidney Injury

by Samiksha Wasnik, Xiaolei Tang, Hongzheng Bi, Amir Abdipour, Edmundo E. Carreon, Brian Sutjiadi, Justin Lyu, Jintao Zhang, Sean Wilson and David J. Baylink

Int. J. Mol. Sci. 2020, 21(11), 4095; https://doi.org/10.3390/ijms21114095 - 8 Jun 2020

Cited by 7 | Viewed by 4153

Abstract

This study was undertaken to test two therapies for acute kidney injury (AKI) prevention, IGF-1, which is renal protective, and BTP-2, which is a calcium entry (SOCE) inhibitor. We utilized lipopolysaccharide (LPS) IP, as a systemic model of AKI and studied in five [...] Read more.

This study was undertaken to test two therapies for acute kidney injury (AKI) prevention, IGF-1, which is renal protective, and BTP-2, which is a calcium entry (SOCE) inhibitor. We utilized lipopolysaccharide (LPS) IP, as a systemic model of AKI and studied in five groups of animals. Three experiments showed that at 7 days: (1) LPS significantly reduced serum IGF-1 and intramuscular IGF-I in vivo gene therapy rescued this deficiency. (2) Next, at the 7-day time point, our combination therapy, compared to the untreated group, caused a significant increase in survival, which was noteworthy because all of the untreated animals died in 72 h. (3) The four pathways associated with inflammation, including (A) increase in cytosolic calcium, (B) elaboration of proinflammatory cytokines, (C) impairment of vascular integrity, and (D) cell injury, were adversely affected in renal tissue by LPS, using a sublethal dose of LPS. The expression of several genes was measured in each of the above pathways. The combined therapy of IGF-1 and BTP-2 caused a favorable gene expression response in all four pathways. Our current study was an AKI study, but these pathways are also involved in other types of severe inflammation, including sepsis, acute respiratory distress syndrome, and probably severe coronavirus infection. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies 2.0)

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22 pages, 12002 KiB

Open AccessArticle

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

by Anton I. Korbut, Iuliia S. Taskaeva, Nataliya P. Bgatova, Natalia A. Muraleva, Nikolai B. Orlov, Maksim V. Dashkin, Anna S. Khotskina, Evgenii L. Zavyalov, Vladimir I. Konenkov, Thomas Klein and Vadim V. Klimontov

Int. J. Mol. Sci. 2020, 21(8), 2987; https://doi.org/10.3390/ijms21082987 - 23 Apr 2020

Cited by 82 | Viewed by 8130

Abstract

Recent data have indicated the emerging role of glomerular autophagy in diabetic kidney disease. We aimed to assess the effect of the SGLT2 inhibitor empagliflozin, the DPP4 inhibitor linagliptin, and their combination, on glomerular autophagy in a model of type 2 diabetes. Eight-week-old [...] Read more.

Recent data have indicated the emerging role of glomerular autophagy in diabetic kidney disease. We aimed to assess the effect of the SGLT2 inhibitor empagliflozin, the DPP4 inhibitor linagliptin, and their combination, on glomerular autophagy in a model of type 2 diabetes. Eight-week-old male db/db mice were randomly assigned to treatment with empagliflozin, linagliptin, empagliflozin–linagliptin or vehicle for 8 weeks. Age-matched non-diabetic db/+ mice acted as controls. To estimate glomerular autophagy, immunohistochemistry for beclin-1 and LAMP-1 was performed. Podocyte autophagy was assessed by counting the volume density (Vv) of autophagosomes, lysosomes and autolysosomes by transmission electron microscopy. LC3B and LAMP-1, autophagy markers, and caspase-3 and Bcl-2, apoptotic markers, were evaluated in renal cortex by western blot. Vehicle-treated db/db mice had weak glomerular staining for beclin-1 and LAMP-1 and reduced Vv of autophagosomes, autolysosomes and lysosomes in podocytes. Empagliflozin and linagliptin, both as monotherapy and in combination, enhanced the areas of glomerular staining for beclin-1 and LAMP-1 and increased Vv of autophagosomes and autolysosomes in podocytes. Renal LC3B and Bcl-2 were restored in actively treated animals. LAMP-1 expression was enhanced in the empagliflozin group; caspase-3 expression decreased in the empagliflozin–linagliptin group only. Mesangial expansion, podocyte foot process effacement and urinary albumin excretion were mitigated by both agents. The data provide further explanation for the mechanism of the renoprotective effect of SGLT2 inhibitors and DPP4 inhibitors in diabetes. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies 2.0)

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12 pages, 2846 KiB

Open AccessArticle

Ipragliflozin Ameliorates Endoplasmic Reticulum Stress and Apoptosis through Preventing Ectopic Lipid Deposition in Renal Tubules

by Kohshiro Hosokawa, Tomoaki Takata, Takaaki Sugihara, Tomomitsu Matono, Masahiko Koda, Tsutomu Kanda, Sosuke Taniguchi, Ayami Ida, Yukari Mae, Marie Yamamoto, Takuji Iyama, Satoko Fukuda and Hajime Isomoto

Int. J. Mol. Sci. 2020, 21(1), 190; https://doi.org/10.3390/ijms21010190 - 26 Dec 2019

Cited by 38 | Viewed by 4615

Abstract

Background: Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health burdens closely related to metabolic syndrome. A link between CKD and NASH has been assumed; however, the underlying mechanism is still unknown. Ectopic lipid deposition (ELD) in the hepatocyte results in [...] Read more.

Background: Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health burdens closely related to metabolic syndrome. A link between CKD and NASH has been assumed; however, the underlying mechanism is still unknown. Ectopic lipid deposition (ELD) in the hepatocyte results in endoplasmic reticulum (ER) stress, which plays an important role in the development of steatohepatitis. ELD is also assumed to play a role in the development of kidney injury. We aimed to investigate the role of ELD and ER stress in the development of CKD, and evaluate the efficacy of a sodium glucose cotransporter-2 inhibitor, ipragliflozin. Methods: Male FLS-ob/ob mice that closely imitate the pathophysiology of NASH were treated with vehicle or ipragliflozin. Metabolic characteristics, histology of the kidney, ER stress, and apoptotic signals were evaluated. Results: The serum triglyceride was significantly lower in mice treated with ipragliflozin. Ipragliflozin reduced ELD in renal tubules. Ipragliflozin also reduced the expression levels of GRP78 and CHOP, apoptotic cells, and interstitial fibrosis. Conclusions: ELD induced kidney injury through ER stress. Ipragliflozin improved the pathogenesis of CKD by reducing ELD and ER stress in NASH-model mice. Our results suggest ipragliflozin has therapeutic effect on CKD in NASH. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies 2.0)

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9 pages, 5297 KiB

Open AccessArticle

Renal Tubular Glucagon-Like Peptide-1 Receptor Expression Is Increased in Early Sepsis but Reduced in Chronic Kidney Disease and Sepsis-Induced Kidney Injury

by Jae Hyun Choi, Seung Jung Kim, Soon Kil Kwon, Hye-Young Kim and Hyunjung Jeon

Int. J. Mol. Sci. 2019, 20(23), 6024; https://doi.org/10.3390/ijms20236024 - 29 Nov 2019

Cited by 8 | Viewed by 3442

Abstract

Acute kidney injury (AKI) is common in patients with sepsis and causes renal ischemia. Glucagon-like peptide-1 (GLP-1) protects the vascular system and the kidney, and GLP-1 receptor (GLP-1R) is expressed in the kidney. Renal GLP-1R activity is decreased in chronic kidney disease (CKD), [...] Read more.

Acute kidney injury (AKI) is common in patients with sepsis and causes renal ischemia. Glucagon-like peptide-1 (GLP-1) protects the vascular system and the kidney, and GLP-1 receptor (GLP-1R) is expressed in the kidney. Renal GLP-1R activity is decreased in chronic kidney disease (CKD), but is increased by the inflammatory response; however, the effect of AKI on GLP-1R expression is unknown. We investigated the role of GLP-1 by assessing GLP-1R expression in the renal cortex in animals with AKI-related sepsis, CKD, and CKD-with-sepsis. We generated a model of CKD by 5/6 nephrectomy, and sepsis induced by cecal perforation, in male Sprague–Dawley rats. We compared renal GLP-1R expression at 3, 6, 12, 24, and 72 h after cecal perforation, and in CKD and CKD-with-sepsis. We performed blood and urine tests, western blotting (WB), and immunohistochemistry (IHC) to assay GLP-1R expression in renal tubules. The CKD-with-sepsis group showed the lowest kidney function, urine volume, and serum glucose and albumin levels. GLP-1R expression in renal tubules was decreased at 3 h, increased at 24 h, and decreased at 72 h after sepsis induction. GLP-1R expression was decreased at 8 weeks after CKD and was lowest in the CKD-with-sepsis group. The WB results were verified against those obtained by IHC. GLP-1R expression in renal tubules is increased in early sepsis, which may explain the protective effect of endogenous GLP-1 against sepsis-related inflammation. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies 2.0)

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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 15 | Viewed by 3155

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, [...] Read more.

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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11 pages, 2136 KiB

Open AccessArticle

The Absence of Endothelial Sodium Channel α (αENaC) Reduces Renal Ischemia/Reperfusion Injury

by Antoine Tarjus, Cecilia González-Rivas, Isabel Amador-Martínez, Benjamin Bonnard, Rebeca López-Marure, Frédéric Jaisser and Jonatan Barrera-Chimal

Int. J. Mol. Sci. 2019, 20(13), 3132; https://doi.org/10.3390/ijms20133132 - 27 Jun 2019

Cited by 19 | Viewed by 3438

Abstract

The epithelial sodium channel (ENaC) has a key role in modulating endothelial cell stiffness and this in turn regulates nitric oxide (NO) synthesis. The physiological relevance of endothelial ENaC in pathological conditions where reduced NO bioavailability plays an essential role remains largely unexplored. [...] Read more.

The epithelial sodium channel (ENaC) has a key role in modulating endothelial cell stiffness and this in turn regulates nitric oxide (NO) synthesis. The physiological relevance of endothelial ENaC in pathological conditions where reduced NO bioavailability plays an essential role remains largely unexplored. Renal ischemia/reperfusion (IR) injury is characterized by vasoconstriction and sustained decrease in renal perfusion that is partially explained by a reduction in NO bioavailability. Therefore, we aimed to explore if an endothelial ENaC deficiency has an impact on the severity of renal injury induced by IR. Male mice with a specific endothelial sodium channel α (αENaC) subunit gene inactivation in the endothelium (endo-αENaC^KO) and control littermates were subjected to bilateral renal ischemia of 22 min and were studied after 24 h of reperfusion. In control littermates, renal ischemia induced an increase in plasma creatinine and urea, augmented the kidney injury molecule-1 (Kim-1) and neutrophil gelatinase associated lipocalin-2 (NGAL) mRNA levels, and produced severe tubular injury. The absence of endothelial αENaC expression prevented renal tubular injury and renal dysfunction. Moreover, endo-αENaC^KO mice recovered faster from renal hypoxia after the ischemia episode as compared to littermates. In human endothelial cells, pharmacological ENaC inhibition promoted endothelial nitric oxide synthase (eNOS) coupling and activation. Altogether, these data suggest an important role for endothelial αENaC in kidney IR injury through improving eNOS activation and kidney perfusion, thus, preventing ischemic injury. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies 2.0)

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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 4607

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) [...] Read more.

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 4157

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. [...] Read more.

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 49 | Viewed by 5176

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 [...] Read more.

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 25 | Viewed by 4225

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 [...] Read more.

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 4791

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 [...] Read more.

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 5533

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 [...] Read more.

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 18 | Viewed by 4514

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 [...] Read more.

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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17 pages, 556 KiB

Open AccessReview

Renal Sympathetic Nerve-Derived Signaling in Acute and Chronic Kidney Diseases

by Mi Ra Noh, Hee-Seong Jang, Jinu Kim and Babu J. Padanilam

Int. J. Mol. Sci. 2020, 21(5), 1647; https://doi.org/10.3390/ijms21051647 - 28 Feb 2020

Cited by 28 | Viewed by 7865

Abstract

The kidney is innervated by afferent sensory and efferent sympathetic nerve fibers. Norepinephrine (NE) is the primary neurotransmitter for post-ganglionic sympathetic adrenergic nerves, and its signaling, regulated through adrenergic receptors (AR), modulates renal function and pathophysiology under disease conditions. Renal sympathetic overactivity and [...] Read more.

The kidney is innervated by afferent sensory and efferent sympathetic nerve fibers. Norepinephrine (NE) is the primary neurotransmitter for post-ganglionic sympathetic adrenergic nerves, and its signaling, regulated through adrenergic receptors (AR), modulates renal function and pathophysiology under disease conditions. Renal sympathetic overactivity and increased NE level are commonly seen in chronic kidney disease (CKD) and are critical factors in the progression of renal disease. Blockade of sympathetic nerve-derived signaling by renal denervation or AR blockade in clinical and experimental studies demonstrates that renal nerves and its downstream signaling contribute to progression of acute kidney injury (AKI) to CKD and fibrogenesis. This review summarizes our current knowledge of the role of renal sympathetic nerve and adrenergic receptors in AKI, AKI to CKD transition and CKDand provides new insights into the therapeutic potential of intervening in its signaling pathways. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies 2.0)

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Graphical abstract

20 pages, 886 KiB

Open AccessReview

IL-20 in Acute Kidney Injury: Role in Pathogenesis and Potential as a Therapeutic Target

by Tian-Yu Lin and Yu-Hsiang Hsu

Int. J. Mol. Sci. 2020, 21(3), 1009; https://doi.org/10.3390/ijms21031009 - 3 Feb 2020

Cited by 26 | Viewed by 10505

Abstract

Acute kidney injury (AKI) causes over 1 million deaths worldwide every year. AKI is now recognized as a major risk factor in the development and progression of chronic kidney disease (CKD). Diabetes is the main cause of CKD as well. Renal fibrosis and [...] Read more.

Acute kidney injury (AKI) causes over 1 million deaths worldwide every year. AKI is now recognized as a major risk factor in the development and progression of chronic kidney disease (CKD). Diabetes is the main cause of CKD as well. Renal fibrosis and inflammation are hallmarks in kidney diseases. Various cytokines contribute to the progression of renal diseases; thus, many drugs that specifically block cytokine function are designed for disease amelioration. Numerous studies showed IL-20 functions as a pro-inflammatory mediator to regulate cytokine expression in several inflammation-mediated diseases. In this review, we will outline the effects of pro-inflammatory cytokines in the pathogenesis of AKI and CKD. We also discuss the role of IL-20 in kidney diseases and provide a potential therapeutic approach of IL-20 blockade for treating renal diseases. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies 2.0)

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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 57 | Viewed by 12139

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 [...] Read more.

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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