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Article ; Online: Transient inhibition of sodium-glucose cotransporter 2 after ischemia/reperfusion injury ameliorates chronic kidney disease.

Martínez-Rojas, Miguel Ángel / Balcázar, Hiram / González-Soria, Isaac / González-Rivera, Jesús Manuel / Rodríguez-Vergara, Mauricio E / Velazquez-Villegas, Laura A / León-Contreras, Juan Carlos / Pérez-Villalva, Rosalba / Correa, Francisco / Rosetti, Florencia / Bobadilla, Norma A

JCI insight

2024 Volume 9, Issue 6

Abstract: Sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (Dapa), exhibited nephroprotective effects in patients with chronic kidney disease (CKD). We assessed the efficacy of short-term Dapa administration following acute kidney injury (AKI) in ... ...

Abstract	Sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (Dapa), exhibited nephroprotective effects in patients with chronic kidney disease (CKD). We assessed the efficacy of short-term Dapa administration following acute kidney injury (AKI) in preventing CKD. Male Wistar rats were randomly assigned to Sham surgery, bilateral ischemia for 30 minutes (abbreviated as IR), and IR + Dapa groups. Daily treatment with Dapa was initiated just 24 hours after IR and maintained for only 10 days. Initially, rats were euthanized at this point to study early renal repair. After severe AKI, Dapa promptly restored creatinine clearance (CrCl) and significantly reduced renal vascular resistance compared with the IR group. Furthermore, Dapa effectively reversed the mitochondrial abnormalities, including increased fission, altered mitophagy, metabolic dysfunction, and proapoptotic signaling. To study this earlier, another set of rats was studied just 5 days after AKI. Despite persistent renal dysfunction, our data reveal a degree of mitochondrial protection. Remarkably, a 10-day treatment with Dapa demonstrated effectiveness in preventing CKD transition in an independent cohort monitored for 5 months after AKI. This was evidenced by improvements in proteinuria, CrCl, glomerulosclerosis, and fibrosis. Our findings underscore the potential of Dapa in preventing maladaptive repair following AKI, emphasizing the crucial role of early intervention in mitigating AKI long-term consequences.
MeSH term(s)	Animals ; Humans ; Male ; Rats ; Acute Kidney Injury/drug therapy ; Acute Kidney Injury/prevention & control ; Acute Kidney Injury/metabolism ; Glucose ; Rats, Wistar ; Renal Insufficiency, Chronic/drug therapy ; Reperfusion Injury/complications ; Reperfusion Injury/metabolism ; Sodium/metabolism ; Sodium-Glucose Transporter 2/drug effects ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; Benzhydryl Compounds/pharmacology ; Benzhydryl Compounds/therapeutic use
Chemical Substances	Glucose (IY9XDZ35W2) ; Sodium (9NEZ333N27) ; Sodium-Glucose Transporter 2 ; dapagliflozin (1ULL0QJ8UC) ; Sodium-Glucose Transporter 2 Inhibitors ; Benzhydryl Compounds
Language	English
Publishing date	2024-02-22
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.173675
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A short treatment with resveratrol after a renal ischaemia-reperfusion injury prevents maladaptive repair and long-term chronic kidney disease in rats.

Martínez-Rojas, Miguel Ángel / Balcázar, Hiram / Ponce-Nava, María Susana / González-Soria, Isaac / Marquina-Castillo, Brenda / Pérez-Villalva, Rosalba / Bobadilla, Norma A

The Journal of physiology

2024 Volume 602, Issue 8, Page(s) 1835–1852

Abstract: Acute kidney injury (AKI) often triggers physiological processes aimed at restoring renal function and architecture. However, this response can become maladaptive, leading to nephron loss and fibrosis. Although the therapeutic effects of resveratrol (RSV) ...

Abstract	Acute kidney injury (AKI) often triggers physiological processes aimed at restoring renal function and architecture. However, this response can become maladaptive, leading to nephron loss and fibrosis. Although the therapeutic effects of resveratrol (RSV) are well established, its impact after AKI and for subsequent chronic kidney disease (CKD) remains unclear. This study assessed whether transient administration of RSV following ischaemia-reperfusion injury (IRI) could prevent the progression to CKD. Forty-one male Wistar rats were assigned randomly to sham surgery, bilateral renal ischaemia for 30 min (IR) or IR+RSV. The RSV treatment commenced 24 h after IRI and continued for 10 days. The rats were studied for either 10 days or 5 months, after which kidney function and structure were evaluated. Mitochondrial homeostasis, oxidant defence and renal inflammation state were also evaluated. Despite having the same severity of AKI, rats receiving RSV for 10 days after IRI exhibited significant improvement in kidney histological injury and reduced inflammation, although renal haemodynamic recovery was less pronounced. Resveratrol effectively prevented the elevation of tubular injury-related molecules and profibrotic signalling with reduced myofibroblast proliferation. Furthermore, RSV substantially improved the antioxidant response and mitochondrial homeostasis. After 5 months, RSV prevented the transition to CKD, as evidenced by the prevention of progressive proteinuria, renal dysfunction and tubulointerstitial fibrosis. This study demonstrates that a brief treatment with RSV following IRI is enough to prevent maladaptive repair and the development of CKD. Our findings highlight the importance of the early days of reperfusion, indicating that maladaptive responses can be reduced effectively following severe AKI. KEY POINTS: Physiological processes activated after acute kidney injury (AKI) can lead to maladaptive responses, causing nephron loss and fibrosis. Prophylactic renoprotection with resveratrol (RSV) has been described in experimental AKI, but its impact after AKI and for subsequent chronic kidney disease (CKD) remains unclear. In this study, we found that histological tubular injury persists 10 days after ischaemia-reperfusion injury and contributes to a failed repair phenotype in proximal tubular cells. Short-term RSV intervention influenced the post-ischaemic repair response and accelerated tubular recovery by reducing oxidative stress and mitochondrial damage. Furthermore, RSV targeted inflammation and profibrotic signalling during the maladaptive response, normalizing both processes. Resveratrol effectively prevented AKI-to-CKD transition even 5 months after the intervention. The study serves as a proof of concept, proposing RSV as a valuable candidate for further translational clinical studies to mitigate AKI-to-CKD transition.
MeSH term(s)	Rats ; Male ; Animals ; Resveratrol/pharmacology ; Resveratrol/therapeutic use ; Rats, Wistar ; Kidney/pathology ; Renal Insufficiency, Chronic/drug therapy ; Renal Insufficiency, Chronic/etiology ; Renal Insufficiency, Chronic/pathology ; Acute Kidney Injury/drug therapy ; Acute Kidney Injury/prevention & control ; Acute Kidney Injury/pathology ; Inflammation/complications ; Reperfusion Injury/drug therapy ; Reperfusion Injury/prevention & control ; Reperfusion Injury/complications ; Fibrosis
Chemical Substances	Resveratrol (Q369O8926L)
Language	English
Publishing date	2024-03-26
Publishing country	England
Document type	Journal Article
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/JP285979
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Article ; Online: Urinary serpin-A3 is an early predictor of clinical response to therapy in patients with proliferative lupus nephritis.

Martínez-Rojas, Miguel Ángel / Sánchez-Navarro, Andrea / Mejia-Vilet, Juan Manuel / Pérez-Villalva, Rosalba / Uribe, Norma / Bobadilla, Norma A

American journal of physiology. Renal physiology

2022 Volume 323, Issue 4, Page(s) F425–F434

Abstract: We have previously reported that urinary excretion of serpin-A3 (uSerpA3) is significantly elevated in patients with active lupus nephritis (LN). Here, we evaluated the course of uSerpA3 during the first year of treatment and its association with ... ...

Abstract	We have previously reported that urinary excretion of serpin-A3 (uSerpA3) is significantly elevated in patients with active lupus nephritis (LN). Here, we evaluated the course of uSerpA3 during the first year of treatment and its association with response to therapy in patients with proliferative LN. The observational longitudinal study included 60 Mexican adults with proliferative LN followed during the first year after LN flare. uSerpA3 was detected by Western blot analysis at flare and after 3, 6, and 12 mo. The response to therapy was determined 1 yr after the LN flare. We evaluated the correlation between uSerpA3 and histological parameters at LN flare. The temporal association between uSerpA3 and response to therapy was analyzed with linear mixed models. uSerpA3 prognostic performance for response was evaluated with receiver-operating characteristic curves. Among the 60 patients studied, 21 patients (35%) were class III and 39 patients (65%) were class IV. uSerpA3 was higher in class IV than in class III LN (6.98 vs. 2.89 dots per in./mg creatinine,
MeSH term(s)	Adult ; Biomarkers/urine ; Creatinine/urine ; Humans ; Inflammation ; Longitudinal Studies ; Lupus Nephritis/diagnosis ; Lupus Nephritis/drug therapy ; Serpins/urine ; alpha 1-Antichymotrypsin/therapeutic use
Chemical Substances	Biomarkers ; Serpins ; alpha 1-Antichymotrypsin ; Creatinine (AYI8EX34EU)
Language	English
Publishing date	2022-07-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00099.2022
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Article ; Online: SerpinA3K Deficiency Reduces Oxidative Stress in Acute Kidney Injury.

González-Soria, Isaac / Soto-Valadez, Axel D / Martínez-Rojas, Miguel Angel / Ortega-Trejo, Juan Antonio / Pérez-Villalva, Rosalba / Gamba, Gerardo / Sánchez-Navarro, Andrea / Bobadilla, Norma A

International journal of molecular sciences

2023 Volume 24, Issue 9

Abstract: We previously showed that SerpinA3K is present in urine from rats and humans with acute kidney injury (AKI) and chronic kidney disease (CKD). However, the specific role of SerpinA3K during renal pathophysiology is unknown. To begin to understand the role ...

Abstract	We previously showed that SerpinA3K is present in urine from rats and humans with acute kidney injury (AKI) and chronic kidney disease (CKD). However, the specific role of SerpinA3K during renal pathophysiology is unknown. To begin to understand the role of SerpinA3K on AKI, SerpinA3K-deficient (KOSA3) mice were studied 24 h after inducing ischemia/reperfusion (I/R) and compared to wild type (WT) mice. Four groups were studied: WT+S, WT+IR, KOSA3+S, and KOSA3+IR. As expected, I/R increased serum creatinine and BUN, with a GFR reduction in both genotypes; however, renal dysfunction was ameliorated in the KOSA3+IR group. Interestingly, the increase in UH
MeSH term(s)	Animals ; Mice ; Acute Kidney Injury/metabolism ; Apoptosis ; Kidney/metabolism ; Oxidative Stress ; Renal Insufficiency, Chronic/metabolism ; Reperfusion Injury/metabolism
Chemical Substances	Serpina3k protein, mouse
Language	English
Publishing date	2023-04-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24097815
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Article ; Online: Is the kidney a target of SARS-CoV-2?

Martinez-Rojas, Miguel Angel / Vega-Vega, Olynka / Bobadilla, Norma A

American journal of physiology. Renal physiology

2020 Volume 318, Issue 6, Page(s) F1454–F1462

Abstract: The new disease produced by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) represents a major pandemic event nowadays. Since its origin in China in December 2019, there is compelling evidence that novel SARS-CoV-2 is a highly transmissible ... ...

Abstract	The new disease produced by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) represents a major pandemic event nowadays. Since its origin in China in December 2019, there is compelling evidence that novel SARS-CoV-2 is a highly transmissible virus, and it is associated to a broad clinical spectrum going from subclinical presentation to severe respiratory distress and multiorgan failure. Like other coronaviruses, SARS-CoV-2 recognizes human angiotensin-converting enzyme 2 as a cellular receptor that allows it to infect different host cells and likely disrupts renin-angiotensin-aldosterone system homeostasis. Particularly, a considerable incidence of many renal abnormalities associated to COVID-19 has been reported, including proteinuria, hematuria, and acute kidney injury. Moreover, it has been recently demonstrated that SARS-CoV-2 can infect podocytes and tubular epithelial cells, which could contribute to the development of the aforementioned renal abnormalities. In this review, we discuss the biological aspects of SARS-CoV-2 infection, how understanding current knowledge about SARS-CoV-2 infection may partly explain the involvement of the kidneys in the pathophysiology of COVID-19, and what questions have arisen and remain to be explored.
MeSH term(s)	Angiotensin-Converting Enzyme 2 ; Betacoronavirus ; COVID-19 ; Coronavirus Infections/complications ; Coronavirus Infections/metabolism ; Humans ; Kidney/virology ; Kidney Diseases/virology ; Pandemics ; Peptidyl-Dipeptidase A/metabolism ; Pneumonia, Viral/complications ; Pneumonia, Viral/metabolism ; SARS-CoV-2
Chemical Substances	Peptidyl-Dipeptidase A (EC 3.4.15.1) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Keywords	covid19
Language	English
Publishing date	2020-05-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00160.2020
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Article ; Online: Sirtuin 7 Deficiency Reduces Inflammation and Tubular Damage Induced by an Episode of Acute Kidney Injury.

Sánchez-Navarro, Andrea / Martínez-Rojas, Miguel Ángel / Albarrán-Godinez, Adrián / Pérez-Villalva, Rosalba / Auwerx, Johan / de la Cruz, Abigail / Noriega, Lilia G / Rosetti, Florencia / Bobadilla, Norma A

International journal of molecular sciences

2022 Volume 23, Issue 5

Abstract: Acute kidney injury (AKI) is a public health problem worldwide. Sirtuins are a family of seven NAD+-dependent deacylases, Overexpression of Sirtuin 1, 3, and 5 protect against AKI. However, the role of Sirtuin 7 (Sirt7) in AKI is not known. Here, we ... ...

Abstract	Acute kidney injury (AKI) is a public health problem worldwide. Sirtuins are a family of seven NAD+-dependent deacylases, Overexpression of Sirtuin 1, 3, and 5 protect against AKI. However, the role of Sirtuin 7 (Sirt7) in AKI is not known. Here, we analyzed how Sirt7 deficient mice (KO-Sirt7) were affected by AKI. As expected, wild-type and Sirt7 heterozygotes mice that underwent renal ischemia/reperfusion (IR) exhibited the characteristic hallmarks of AKI: renal dysfunction, tubular damage, albuminuria, increased oxidative stress, and renal inflammation. In contrast, the KO-Sirt7+IR mice were protected from AKI, exhibiting lesser albuminuria and reduction in urinary biomarkers of tubular damage, despite similar renal dysfunction. The renoprotection in the Sirt7-KO+IR group was associated with reduced kidney weight, minor expression of inflammatory cytokines and less renal infiltration of inflammatory cells. This anti-inflammatory effect was related to diminished p65 expression and in its active phosphorylation, as well as by a reduction in p65 nuclear translocation. Sirt7 deficient mice are protected from AKI, suggesting that this histone deacetylase promotes tubular damage and renal inflammation. Therefore, our findings indicate that Sirt7 inhibitors may be an attractive therapeutic target to reduce NFκB signaling.
MeSH term(s)	Acute Kidney Injury/metabolism ; Albuminuria ; Animals ; Inflammation/metabolism ; Kidney/metabolism ; Mice ; Mice, Inbred C57BL ; Reperfusion Injury/metabolism ; Sirtuins/genetics ; Sirtuins/metabolism
Chemical Substances	Sirt7 protein, mouse ; Sirtuins (EC 3.5.1.-)
Language	English
Publishing date	2022-02-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23052573
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Article ; Online: Comparative transcriptome analysis identifies CARM1 and DNMT3A as genes associated with osteoporosis.

Panach, Layla / Pertusa, Clara / Martínez-Rojas, Beatriz / Acebrón, Álvaro / Mifsut, Damián / Tarín, Juan J / Cano, Antonio / García-Pérez, Miguel Ángel

Scientific reports

2020 Volume 10, Issue 1, Page(s) 16298

Abstract: To identify new candidate genes in osteoporosis, mainly involved in epigenetic mechanisms, we compared whole gene-expression in osteoblasts (OBs) obtained from women undergoing hip replacement surgery due to fragility fracture and severe osteoarthritis. ... ...

Abstract	To identify new candidate genes in osteoporosis, mainly involved in epigenetic mechanisms, we compared whole gene-expression in osteoblasts (OBs) obtained from women undergoing hip replacement surgery due to fragility fracture and severe osteoarthritis. Then, we analyzed the association of several SNPs with BMD in 1028 women. Microarray analysis yielded 2542 differentially expressed transcripts belonging to 1798 annotated genes, of which 45.6% (819) were overexpressed, and 54.4% (979) underexpressed (fold-change between - 7.45 and 4.0). Among the most represented pathways indicated by transcriptome analysis were chondrocyte development, positive regulation of bone mineralization, BMP signaling pathway, skeletal system development and Wnt signaling pathway. In the translational stage we genotyped 4 SNPs in DOT1L, HEY2, CARM1 and DNMT3A genes. Raw data analyzed against inheritance patterns showed a statistically significant association between a SNP of DNMT3A and femoral neck-(FN) sBMD and primarily a SNP of CARM1 was correlated with both FN and lumbar spine-(LS) sBMD. Most of these associations remained statistically significant after adjusting for confounders. In analysis with anthropometric and clinical variables, the SNP of CARM1 unexpectedly revealed a close association with BMI (p = 0.000082), insulin (p = 0.000085), and HOMA-
MeSH term(s)	Bone Density/genetics ; CARD Signaling Adaptor Proteins/genetics ; Case-Control Studies ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA Methyltransferase 3A ; Gene Expression Profiling/methods ; Genetic Predisposition to Disease/genetics ; Guanylate Cyclase/genetics ; Humans ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; Osteoporosis/genetics ; Osteoporotic Fractures/genetics ; Polymorphism, Single Nucleotide/genetics ; Real-Time Polymerase Chain Reaction ; Transcriptome
Chemical Substances	CARD Signaling Adaptor Proteins ; DNMT3A protein, human ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNA Methyltransferase 3A (EC 2.1.1.37) ; CARD11 protein, human (EC 4.6.1.2) ; Guanylate Cyclase (EC 4.6.1.2)
Language	English
Publishing date	2020-10-01
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-72870-2
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Article ; Online: Sirtuin 7 Deficiency Reduces Inflammation and Tubular Damage Induced by an Episode of Acute Kidney Injury

Andrea Sánchez-Navarro / Miguel Ángel Martínez-Rojas / Adrián Albarrán-Godinez / Rosalba Pérez-Villalva / Johan Auwerx / Abigail de la Cruz / Lilia G. Noriega / Florencia Rosetti / Norma A. Bobadilla

International Journal of Molecular Sciences, Vol 23, Iss 2573, p

2022 Volume 2573

Abstract	Acute kidney injury (AKI) is a public health problem worldwide. Sirtuins are a family of seven NAD+-dependent deacylases, Overexpression of Sirtuin 1, 3, and 5 protect against AKI. However, the role of Sirtuin 7 (Sirt7) in AKI is not known. Here, we analyzed how Sirt7 deficient mice (KO-Sirt7) were affected by AKI. As expected, wild-type and Sirt7 heterozygotes mice that underwent renal ischemia/reperfusion (IR) exhibited the characteristic hallmarks of AKI: renal dysfunction, tubular damage, albuminuria, increased oxidative stress, and renal inflammation. In contrast, the KO-Sirt7+IR mice were protected from AKI, exhibiting lesser albuminuria and reduction in urinary biomarkers of tubular damage, despite similar renal dysfunction. The renoprotection in the Sirt7-KO+IR group was associated with reduced kidney weight, minor expression of inflammatory cytokines and less renal infiltration of inflammatory cells. This anti-inflammatory effect was related to diminished p65 expression and in its active phosphorylation, as well as by a reduction in p65 nuclear translocation. Sirt7 deficient mice are protected from AKI, suggesting that this histone deacetylase promotes tubular damage and renal inflammation. Therefore, our findings indicate that Sirt7 inhibitors may be an attractive therapeutic target to reduce NFκB signaling.
Keywords	histone deacetylase ; NFkB signaling ; immune cells infiltration ; tubular injury ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Early triggers of moderately high-fat diet-induced kidney damage.

Sánchez-Navarro, Andrea / Martínez-Rojas, Miguel Ángel / Caldiño-Bohn, Rebecca I / Pérez-Villalva, Rosalba / Zambrano, Elena / Castro-Rodríguez, Diana C / Bobadilla, Norma A

Physiological reports

2021 Volume 9, Issue 14, Page(s) e14937

Abstract: Most of the obesity murine models inducing renal injury use calorie-enriched foods, where fat represents 60% of the total caloric supply, however, this strategy doubles the standard proportion of fat ingestion in obese patients. Therefore, it is crucial ... ...

Abstract	Most of the obesity murine models inducing renal injury use calorie-enriched foods, where fat represents 60% of the total caloric supply, however, this strategy doubles the standard proportion of fat ingestion in obese patients. Therefore, it is crucial to study the impact of a high-fat intake on kidney physiology that resembles common obesity in humans to understand the trigger mechanisms of the long-term consequences of overweight and obesity. In this study, we analyzed whether chronic feeding with a moderately high fat diet (MHFD) representing 45% of total calories, may induce kidney function and structural injury compared to C57BL/6 mice fed a control diet. After 14 weeks, MHFD induced significant mice obesity. At the functional level, obese mice showed signs of kidney injury characterized by increased albuminuria/creatinine ratio and higher excretion of urinary biomarkers of kidney damage. While, at the structural level, glomerular hypertrophy was observed. Although, we did not detect renal fibrosis, the obese mice exhibited a significant elevation of Tgfb1 mRNA levels. Kidney damage caused by the exposure to MHFD was associated with greater oxidative stress, renal inflammation, higher endoplasmic reticulum (ER)-stress, and disruption of mitochondrial dynamics. In summary, our data demonstrate that obesity induced by a milder fat content diet is enough to establish renal injury, where oxidative stress, inflammation, ER-stress, and mitochondrial damage take relevance, pointing out the importance of opportune interventions to avoid the long-term consequences associated with obesity and metabolic syndrome.
MeSH term(s)	Animals ; Diet, High-Fat/adverse effects ; Kidney Diseases/etiology ; Kidney Diseases/metabolism ; Kidney Diseases/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Obesity/etiology ; Obesity/metabolism ; Obesity/pathology ; Oxidative Stress/physiology
Language	English
Publishing date	2021-07-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2724325-4
ISSN	2051-817X ; 2051-817X
ISSN (online)	2051-817X
ISSN	2051-817X
DOI	10.14814/phy2.14937
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Article ; Online: Vegfa promoter gene hypermethylation at HIF1α binding site is an early contributor to CKD progression after renal ischemia.

Sánchez-Navarro, Andrea / Pérez-Villalva, Rosalba / Murillo-de-Ozores, Adrián Rafael / Martínez-Rojas, Miguel Ángel / Rodríguez-Aguilera, Jesús Rafael / González, Norma / Castañeda-Bueno, María / Gamba, Gerardo / Recillas-Targa, Félix / Bobadilla, Norma A

Scientific reports

2021 Volume 11, Issue 1, Page(s) 8769

Abstract: Chronic hypoxia is a major contributor to Chronic Kidney Disease (CKD) after Acute Kidney Injury (AKI). However, the temporal relation between the acute insult and maladaptive renal response to hypoxia remains unclear. In this study, we analyzed the time- ...

Abstract	Chronic hypoxia is a major contributor to Chronic Kidney Disease (CKD) after Acute Kidney Injury (AKI). However, the temporal relation between the acute insult and maladaptive renal response to hypoxia remains unclear. In this study, we analyzed the time-course of renal hemodynamics, oxidative stress, inflammation, and fibrosis, as well as epigenetic modifications, with focus on HIF1α/VEGF signaling, in the AKI to CKD transition. Sham-operated, right nephrectomy (UNx), and UNx plus renal ischemia (IR + UNx) groups of rats were included and studied at 1, 2, 3, or 4 months. The IR + UNx group developed CKD characterized by progressive proteinuria, renal dysfunction, tubular proliferation, and fibrosis. At first month post-ischemia, there was a twofold significant increase in oxidative stress and reduction in global DNA methylation that was maintained throughout the study. Hif1α and Vegfa expression were depressed in the first and second-months post-ischemia, and then Hif1α but not Vegfa expression was recovered. Interestingly, hypermethylation of the Vegfa promoter gene at the HIF1α binding site was found, since early stages of the CKD progression. Our findings suggest that renal hypoperfusion, inefficient hypoxic response, increased oxidative stress, DNA hypomethylation, and, Vegfa promoter gene hypermethylation at HIF1α binding site, are early determinants of AKI-to-CKD transition.
MeSH term(s)	Acute Kidney Injury/pathology ; Animals ; DNA Methylation ; Disease Progression ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Ischemia/pathology ; Kidney/blood supply ; Male ; Oxidative Stress ; Promoter Regions, Genetic ; Rats ; Rats, Wistar ; Renal Insufficiency, Chronic/genetics ; Renal Insufficiency, Chronic/metabolism ; Renal Insufficiency, Chronic/pathology ; Vascular Endothelial Growth Factor A/genetics
Chemical Substances	Hif1a protein, rat ; Hypoxia-Inducible Factor 1, alpha Subunit ; Vascular Endothelial Growth Factor A ; vascular endothelial growth factor A, rat
Language	English
Publishing date	2021-04-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-88000-5
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