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22 pages, 5598 KiB

Open AccessArticle

Gender-Specific Renoprotective Pathways in αMUPA Transgenic Mice Subjected to Acute Kidney Injury

by Heba Abd Alkhaleq, Shadi Hamoud, Israel Hacker, Tony Karram, Ahmad Fokra, Aviva Kabala and Zaid Abassi

Int. J. Mol. Sci. 2024, 25(6), 3544; https://doi.org/10.3390/ijms25063544 - 21 Mar 2024

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Abstract

Acute kidney injury (AKI) is a serious health concern with high morbidity and high mortality worldwide. Recently, sexual dimorphism has become increasingly recognized as a factor influencing the severity of the disease. This study explores the gender-specific renoprotective pathways in αMUPA transgenic mice [...] Read more.

Acute kidney injury (AKI) is a serious health concern with high morbidity and high mortality worldwide. Recently, sexual dimorphism has become increasingly recognized as a factor influencing the severity of the disease. This study explores the gender-specific renoprotective pathways in αMUPA transgenic mice subjected to AKI. αMUPA transgenic male and female mice were subjected to ischemia–reperfusion (I/R)-AKI in the presence or absence of orchiectomy, oophorectomy, and L-NAME administration. Blood samples and kidneys were harvested 48 h following AKI for the biomarkers of kidney function, renal injury, inflammatory response and intracellular pathway sensing of or responding to AKI. Our findings show differing responses to AKI, where female αMUPA mice were remarkably protected against AKI as compared with males, as was evident by the lower SCr and BUN, normal renal histologically and attenuated expression of NGAL and KIM-1. Moreover, αMUPA females did not show a significant change in the renal inflammatory and fibrotic markers following AKI as compared with wild-type (WT) mice and αMUPA males. Interestingly, oophorectomized females eliminated the observed resistance to renal injury, highlighting the central protective role of estrogen. Correspondingly, orchiectomy in αMUPA males mitigated their sensitivity to renal damage, thereby emphasizing the devastating effects of testosterone. Additionally, treatment with L-NAME proved to have significant deleterious impacts on the renal protective mediators, thereby underscoring the involvement of eNOS. In conclusion, gender-specific differences in the response to AKI in αMUPA mice include multifaceted and keen interactions between the sex hormones and key biochemical mediators (such as estrogen, testosterone and eNOS). These novel findings shed light on the renoprotective pathways and mechanisms, which may pave the way for development of therapeutic interventions. Full article

(This article belongs to the Special Issue Pathophysiology of Acute Kidney Injury)

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14 pages, 3690 KiB

Open AccessArticle

SerpinA3K Deficiency Reduces Oxidative Stress in Acute Kidney Injury

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

Int. J. Mol. Sci. 2023, 24(9), 7815; https://doi.org/10.3390/ijms24097815 - 25 Apr 2023

Cited by 3 | Viewed by 1352

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 [...] Read more.

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 UH₂O₂ induced by I/R was not equally seen in the KOSA3+IR group, an effect that was associated with the preservation of antioxidant enzymes’ mRNA levels. Additionally, FOXO3 expression was initially greater in the KOSA3 than in the WT group. Moreover, the increase in BAX protein level and the decrease in Hif1a and Vegfa induced by I/R were not observed in the KOSA3+IR group, suggesting that these animals have better cellular responses to hypoxic injury. Our findings suggest that SerpinA3K is involved in the renal oxidant response, HIF1α/VEGF pathway, and cell apoptosis. Full article

(This article belongs to the Special Issue Pathophysiology of Acute Kidney Injury)

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21 pages, 14302 KiB

Open AccessArticle

Circulating Soluble Urokinase Plasminogen Activator Receptor as a Predictive Indicator for COVID-19-Associated Acute Kidney Injury and Mortality: Clinical and Bioinformatics Analysis

by Hidi A. A. Abdellatif, Basma Osman Sultan, Hassnaa M. Nassar, Mostafa Elsaied Elsayed Gomaa, Mohamed Gamal Sakr, Eman Riad, Alhanouf I. Al-Harbi, Jawaher A. Abdulhakim, Manal S. Fawzy and Noha M. Abd El-Fadeal

Int. J. Mol. Sci. 2023, 24(8), 7177; https://doi.org/10.3390/ijms24087177 - 13 Apr 2023

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Abstract

Urokinase receptors regulate the interplay between inflammation, immunity, and blood clotting. The soluble urokinase plasminogen activator system is an immunologic regulator affecting endothelial function and its related receptor; the soluble urokinase plasminogen activator receptor (suPAR) has been reported to impact kidney injury. This [...] Read more.

Urokinase receptors regulate the interplay between inflammation, immunity, and blood clotting. The soluble urokinase plasminogen activator system is an immunologic regulator affecting endothelial function and its related receptor; the soluble urokinase plasminogen activator receptor (suPAR) has been reported to impact kidney injury. This work aims to measure serum levels of suPAR in COVID-19 patients and correlate the measurements with variable clinicolaboratory parameters and patient outcomes. In this prospective cohort study, 150 COVID-19 patients and 50 controls were included. The circulating suPAR levels were quantified by Enzyme-linked immunosorbent assay (ELISA). Routine COVID-19 laboratory assessments, including CBC, CRP, LDH, serum creatinine, and estimated glomerular filtration rates, were performed. The need for oxygen therapy, CO-RAD score, and survival rates was assessed. Bioinformatic analysis and molecular docking were run to explore the urokinase receptor structure/function and to characterize molecules as potential anti-suPAR therapeutic targets, respectively. We found higher circulating suPAR levels in COVID-19 patients vs. controls (p < 0.001). Circulating suPAR levels positively correlated with COVID-19 severity, the need for O₂ therapy, the total leukocytes count, and the neutrophils to lymphocyte ratio, while they were negatively correlated with the O₂ saturation level, albumin, blood calcium, lymphocytic count, and GFR. In addition, the suPAR levels were associated with poor prognostic outcomes such as a high incidence of acute kidney injury (AKI) and mortality rate. Kaplan–Meier curves showed a lower survival rate with higher suPAR levels. The logistic regression analysis confirmed the significant association of suPAR levels with the occurrence of AKI related to COVID-19 and with increased mortality probability within three months of COVID-19 follow-up. Some compounds that can act similarly to uPAR were discovered and tested by molecular docking to identify the possible ligand–protein interactions. In conclusion, higher circulating suPAR levels were associated with COVID-19 severity and could be considered a putative predictor of AKI development and mortality. Full article

(This article belongs to the Special Issue Pathophysiology of Acute Kidney Injury)

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14 pages, 8835 KiB

Open AccessArticle

The Reduction of Uromodulin, Complement Factor H, and Their Interaction Is Associated with Acute Kidney Injury to Chronic Kidney Disease Transition in a Four-Time Cisplatin-Injected Rat Model

by Zheyu Xing, Kunjing Gong, Nan Hu and Yuqing Chen

Int. J. Mol. Sci. 2023, 24(7), 6636; https://doi.org/10.3390/ijms24076636 - 02 Apr 2023

Cited by 2 | Viewed by 1506

Abstract

Uromodulin is recognized as a protective factor during AKI-to-CKD progression, but the mechanism remains unclear. We previously reported that uromodulin interacts with complement factor H (CFH) in vitro, and currently aimed to study the expression and interaction evolution of uromodulin and CFH during [...] Read more.

Uromodulin is recognized as a protective factor during AKI-to-CKD progression, but the mechanism remains unclear. We previously reported that uromodulin interacts with complement factor H (CFH) in vitro, and currently aimed to study the expression and interaction evolution of uromodulin and CFH during AKI-to-CKD transition. We successfully established a rat model of AKI-to-CKD transition induced by a four-time cisplatin treatment. The blood levels of BUN, SCR, KIM-1 and NGAL increased significantly during the acute injury phase and exhibited an uptrend in chronic progression. PAS staining showed the nephrotoxic effects of four-time cisplatin injection on renal tubules, and Sirius red highlighted the increasing collagen fiber. Protein and mRNA levels of uromodulin decreased while urine levels increased in acute renal injury on chronic background. An extremely diminished level of uromodulin correlated with severe renal fibrosis. RNA sequencing revealed an upregulation of the alternative pathway in the acute stage. Renal CFH gene expression showed an upward tendency, while blood CFH localized less, decreasing the abundance of CFH in kidney and following sustained C3 deposition. A co-IP assay detected the linkage between uromodulin and CFH. In the model of AKI-to-CKD transition, the levels of uromodulin and CFH decreased, which correlated with kidney dysfunction and fibrosis. The interaction between uromodulin and CFH might participate in AKI-to-CKD transition. Full article

(This article belongs to the Special Issue Pathophysiology of Acute Kidney Injury)

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12 pages, 2024 KiB

Open AccessArticle

Association between 20% Albumin Use and Acute Kidney Injury in Major Abdominal Surgery with Transfusion

by Hye Jin Kim, Hyun Joo Kim, Jin Ha Park, Hye Jung Shin, Sung Kyung Yu, Yun Ho Roh, Soo Yeon Jeon and So Yeon Kim

Int. J. Mol. Sci. 2023, 24(3), 2333; https://doi.org/10.3390/ijms24032333 - 25 Jan 2023

Viewed by 2163

Abstract

Red blood cell (RBC) transfusion and albumin administration can affect kidney function. We aimed to evaluate the association between intraoperative 20% albumin administration and acute kidney injury (AKI), along with the duration of hospitalization and 30-day mortality in patients undergoing major abdominal surgery [...] Read more.

Red blood cell (RBC) transfusion and albumin administration can affect kidney function. We aimed to evaluate the association between intraoperative 20% albumin administration and acute kidney injury (AKI), along with the duration of hospitalization and 30-day mortality in patients undergoing major abdominal surgery with RBC transfusion. This retrospective study included 2408 patients who received transfusions during major abdominal surgery. Patients were categorized into albumin (n = 842) or no-albumin (n = 1566) groups. We applied inverse probability of treatment weighting (IPTW), propensity score (PS) matching (PSM), and PS covariate adjustment to assess the effect of albumin administration on the outcomes. In the unadjusted cohort, albumin administration was significantly associated with increased risk of AKI, prolonged hospitalization, and higher 30-day mortality. However, there was no significant association between albumin administration and AKI after adjustment (OR 1.26, 95% CI 0.90–1.76 for the IPTW; OR 1.03, 95% CI 0.72–1.48 for the PSM; and OR 1.04, 95% CI 0.76–1.43 for the PS covariate adjustment methods). While albumin exposure remained associated with prolonged hospitalization after adjustment, it did not affect 30-day mortality. Our findings suggest that hyper-oncotic albumin can be safely administered to patients who are at risk of developing AKI due to RBC transfusion. Full article

(This article belongs to the Special Issue Pathophysiology of Acute Kidney Injury)

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16 pages, 13098 KiB

Open AccessArticle

Repeated Episodes of Ischemia/Reperfusion Induce Heme-Oxygenase-1 (HO-1) and Anti-Inflammatory Responses and Protects against Chronic Kidney Disease

by Juan Antonio Ortega-Trejo, Rosalba Pérez-Villalva, Andrea Sánchez-Navarro, Brenda Marquina, Bernardo Rodríguez-Iturbe and Norma A. Bobadilla

Int. J. Mol. Sci. 2022, 23(23), 14573; https://doi.org/10.3390/ijms232314573 - 23 Nov 2022

Cited by 5 | Viewed by 1455

Abstract

Preconditioning episodes of ischemia/reperfusion (IR) induce protection against acute kidney injury (AKI), however their long-term effect still unknown. We evaluated AKI to chronic kidney disease (CKD) transition, after three-mild or three-severe episodes of IR. AKI was induced by single bilateral IR (1IR), or [...] Read more.

Preconditioning episodes of ischemia/reperfusion (IR) induce protection against acute kidney injury (AKI), however their long-term effect still unknown. We evaluated AKI to chronic kidney disease (CKD) transition, after three-mild or three-severe episodes of IR. AKI was induced by single bilateral IR (1IR), or three episodes of IR separated by 10-day intervals (3IR) of mild (20 min) or severe (45 min) ischemia. Sham-operated rats served as controls. During 9-months, the 1IR group (20 or 45 min) developed CKD evidenced by progressive proteinuria and renal fibrosis. In contrast, the long-term adverse effects of AKI were markedly ameliorated in the 3IR group. The acute response in 3IR, contrasted with the 1IR group, that was characterized by an increment in heme oxygenase-1 (HO-1) and an anti-inflammatory response mediated by a NFkB-p65 phosphorylation and IL-6 decrease, together with an increase in TGF-β, and IL-10 expression, as well as in M2-macrophages. In addition, three episodes of IR downregulated endoplasmic reticulum (ER) stress markers expression, CHOP and BiP. Thus, repeated episodes of IR with 10-day intervals induced long-term renal protection accompanied with HO-1 overexpression and M2-macrophages increase. Full article

(This article belongs to the Special Issue Pathophysiology of Acute Kidney Injury)

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Review

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22 pages, 1626 KiB

Open AccessReview

From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease

by Tzu-Hsuan Yeh, Kuan-Chieh Tu, Hsien-Yi Wang and Jui-Yi Chen

Int. J. Mol. Sci. 2024, 25(3), 1755; https://doi.org/10.3390/ijms25031755 - 01 Feb 2024

Viewed by 1595

Abstract

This article provides a thorough overview of the biomarkers, pathophysiology, and molecular pathways involved in the transition from acute kidney injury (AKI) and acute kidney disease (AKD) to chronic kidney disease (CKD). It categorizes the biomarkers of AKI into stress, damage, and functional [...] Read more.

This article provides a thorough overview of the biomarkers, pathophysiology, and molecular pathways involved in the transition from acute kidney injury (AKI) and acute kidney disease (AKD) to chronic kidney disease (CKD). It categorizes the biomarkers of AKI into stress, damage, and functional markers, highlighting their importance in early detection, prognosis, and clinical applications. This review also highlights the links between renal injury and the pathophysiological mechanisms underlying AKI and AKD, including renal hypoperfusion, sepsis, nephrotoxicity, and immune responses. In addition, various molecules play pivotal roles in inflammation and hypoxia, triggering maladaptive repair, mitochondrial dysfunction, immune system reactions, and the cellular senescence of renal cells. Key signaling pathways, such as Wnt/β-catenin, TGF-β/SMAD, and Hippo/YAP/TAZ, promote fibrosis and impact renal function. The renin–angiotensin–aldosterone system (RAAS) triggers a cascade leading to renal fibrosis, with aldosterone exacerbating the oxidative stress and cellular changes that promote fibrosis. The clinical evidence suggests that RAS inhibitors may protect against CKD progression, especially post-AKI, though more extensive trials are needed to confirm their full impact. Full article

(This article belongs to the Special Issue Pathophysiology of Acute Kidney Injury)

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23 pages, 854 KiB

Open AccessReview

Is Renal Ischemic Preconditioning an Alternative to Ameliorate the Short- and Long-Term Consequences of Acute Kidney Injury?

by Juan Antonio Ortega-Trejo and Norma A. Bobadilla

Int. J. Mol. Sci. 2023, 24(9), 8345; https://doi.org/10.3390/ijms24098345 - 06 May 2023

Viewed by 1921

Abstract

Acute kidney injury (AKI) is a global health problem and has recently been recognized as a risk factor for developing chronic kidney disease (CKD). Unfortunately, there are no effective treatments to reduce or prevent AKI, which results in high morbidity and mortality rates. [...] Read more.

Acute kidney injury (AKI) is a global health problem and has recently been recognized as a risk factor for developing chronic kidney disease (CKD). Unfortunately, there are no effective treatments to reduce or prevent AKI, which results in high morbidity and mortality rates. Ischemic preconditioning (IPC) has emerged as a promising strategy to prevent, to the extent possible, renal tissue from AKI. Several studies have used this strategy, which involves short or long cycles of ischemia/reperfusion (IR) prior to a potential fatal ischemic injury. In most of these studies, IPC was effective at reducing renal damage. Since the first study that showed renoprotection due to IPC, several studies have focused on finding the best strategy to activate correctly and efficiently reparative mechanisms, generating different modalities with promising results. In addition, the studies performing remote IPC, by inducing an ischemic process in distant tissues before a renal IR, are also addressed. Here, we review in detail existing studies on IPC strategies for AKI pathophysiology and the proposed triggering mechanisms that have a positive impact on renal function and structure in animal models of AKI and in humans, as well as the prospects and challenges for its clinical application. Full article

(This article belongs to the Special Issue Pathophysiology of Acute Kidney Injury)

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