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Molecular Mechanisms of Kidney Injury 2.0
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Molecular Mechanisms of Kidney Injury 2.0

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 (30 September 2023) | Viewed by 15743

Special Issue Editor

Dr. Rossana Franzin

E-Mail Website
Guest Editor
Department of Emergency and Organ Transplantation, University of Bari, 70121 Bari, Italy
Interests: acute kidney injury; renal aging; complement system; renal transplantation; endothelial-to-mesenchymal transition
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Renal disease is defined as a heterogeneous group of disorders affecting kidney structure and function. Acute kidney injury (AKI) is a complex syndrome that occurs in critically ill patients and has different etiologies such as sepsis, ischemia reperfusion (I/R) injury, nephrotoxin exposition or major surgery. Other factors, including diabetic status, hypertension, hypoxia, activation of the complement system, can lead to progression of chronic nephropathies. In recent years, research efforts have led to the hypothesis that each type of kidney injury, occurring in distinct kidney compartments (on endothelium, tubular, mesangial cells and podocytes, M1/M2 macrophages), preferentially activates pathway involved in inflammation, premature aging, CKD progression or cellular regeneration and survival. In addition, soluble factors released by damaged renal cells, extracellular vesicles or resident progenitor/stem cells could have an effect on the regulation of a pro-injury microenvironment. Deciphering the molecular mechanism of action underlying kidney injury and repair would provide early biomarkers to predict clinical outcome and targeted therapies to prevent the injury and delay the progression to chronic kidney disease. In this Special Issue, we will publish original research and reviews that would offer new insights into the molecular mechanisms of renal damage with a close scrutiny on factors acting as bifurcation point versus progression to CKD or kidney repair. 

Dr. Rossana Franzin
Guest Editor

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Keywords

  • acute kidney injury
  • chronic kidney injury
  • endothelial dysfunction
  • DNA damage
  • cellular senescence
  • fibrosis
  • senescence
  • extracellular vesicles
  • regeneration progenitors
  • complement system
  • autophagy
  • macrophages

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Related Special Issue

Published Papers (6 papers)

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Research

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12 pages, 2367 KiB  
Article
Longitudinal Follow-Up of Serum and Urine Biomarkers Indicative of COVID-19-Associated Acute Kidney Injury: Diagnostic and Prognostic Impacts
by Yahya Lablad, Charlotte Vanhomwegen, Eric De Prez, Marie-Hélène Antoine, Sania Hasan, Thomas Baudoux and Joëlle Nortier
Int. J. Mol. Sci. 2023, 24(22), 16495; https://doi.org/10.3390/ijms242216495 - 18 Nov 2023
Cited by 3 | Viewed by 1289
Abstract
In patients hospitalized for severe COVID-19, the incidence of acute kidney injury (AKI) is approximately 40%. To predict and understand the implications of this complication, various blood and urine biomarkers have been proposed, including neutrophil gelatinase-associated lipocalin (NGAL), chemokine (C-C motif) ligand 14 [...] Read more.
In patients hospitalized for severe COVID-19, the incidence of acute kidney injury (AKI) is approximately 40%. To predict and understand the implications of this complication, various blood and urine biomarkers have been proposed, including neutrophil gelatinase-associated lipocalin (NGAL), chemokine (C-C motif) ligand 14 (CCL14), cystatin C, leucine aminopeptidase (LAP), and soluble urokinase plasminogen activator (suPAR). This study, conducted between mid-January and early May 2021, aimed to assess the diagnostic and prognostic capabilities of these biomarkers in a cohort of COVID-19 patients monitored during the initial two weeks of hospitalization. Among the 116 patients included in this study, 48 developed AKI within the first three days of hospitalization (41%), with 29 requiring intensive care unit (ICU) admission, and the overall mortality rate was 18%. AKI patients exhibited a statistically significant increase in urinary LAP levels, indicating acute tubular injury as a potential mechanism underlying COVID-19-related renal damage. Conversely, urinary NGAL and CCL-14 excretion rates did not differ significantly between the AKI and non-AKI groups. Importantly, elevated plasma suPAR and cystatin C levels upon admission persisted throughout the first week of hospitalization and were associated with unfavorable outcomes, such as prolonged ICU stays and increased mortality, irrespective of AKI development. In conclusion, this study underscores the early predictive value of urinary LAP levels in identifying acute tubular injury in COVID-19-induced AKI. Moreover, elevated plasma suPAR and cystatin C levels serve as valuable prognostic markers, offering insights into the short-term morbidity and mortality risks among COVID-19 patients, regardless of AKI occurrence. These findings shed light on the complex interplay between COVID-19, renal injury, and biomarkers with diagnostic and prognostic potential. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury 2.0)
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13 pages, 3066 KiB  
Article
Elevation of Arginase-II in Podocytes Contributes to Age-Associated Albuminuria in Male Mice
by Guillaume Ajalbert, Andrea Brenna, Xiu-Fen Ming, Zhihong Yang and Duilio M. Potenza
Int. J. Mol. Sci. 2023, 24(13), 11228; https://doi.org/10.3390/ijms241311228 - 7 Jul 2023
Viewed by 1365
Abstract
One of the manifestations of renal aging is podocyte dysfunction and loss, which are associated with proteinuria and glomerulosclerosis. Studies show a male bias in glomerular dysfunction and chronic kidney diseases, and the underlying mechanisms remain obscure. Recent studies demonstrate the role of [...] Read more.
One of the manifestations of renal aging is podocyte dysfunction and loss, which are associated with proteinuria and glomerulosclerosis. Studies show a male bias in glomerular dysfunction and chronic kidney diseases, and the underlying mechanisms remain obscure. Recent studies demonstrate the role of an age-associated increase in arginase-II (Arg-II) in proximal tubules of both male and female mice. However, it is unclear whether Arg-II is also involved in aging glomeruli. The current study investigates the role of the sex-specific elevation of Arg-II in podocytes in age-associated increased albuminuria. Young (3–4 months) and old (20–22 months) male and female mice of wt and arginase-II knockout (arg-ii−/−) were used. Albuminuria was employed as a readout of glomerular function. Cellular localization and expression of Arg-II in glomeruli were analyzed using an immunofluorescence confocal microscope. A more pronounced age-associated increase in albuminuria was found in male than in female mice. An age-associated induction of Arg-II in glomeruli and podocytes (as demonstrated by co-localization of Arg-II with the podocyte marker synaptopodin) was also observed in males but not in females. Ablation of the arg-ii gene in mice significantly reduces age-associated albuminuria in males. Also, age-associated decreases in podocyte density and glomerulus hypertrophy are significantly prevented in male arg-ii−/− but not in female mice. However, age-associated glomerulosclerosis is not affected by arg-ii ablation in both sexes. These results demonstrate a role of Arg-II in sex-specific podocyte injury in aging. They may explain the sex-specific differences in the development of renal disease in humans during aging. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury 2.0)
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18 pages, 7267 KiB  
Article
Incomplete Recovery from the Radiocontrast-Induced Dysregulated Cell Cycle, Adhesion, and Fibrogenesis in Renal Tubular Cells after Radiocontrast (Iohexol) Removal
by Hsing-Yu Chen, Yi-Hong Wu, Cheng-Yu Wei, Zhi-Yao Liao, Hsiao-Ting Wu, Yung-Chang Chen and Jong-Hwei S. Pang
Int. J. Mol. Sci. 2023, 24(13), 10945; https://doi.org/10.3390/ijms241310945 - 30 Jun 2023
Cited by 1 | Viewed by 1420
Abstract
Contrast-induced nephropathy (CIN) is one of the most common causes of acute kidney injury (AKI). However, management is still limited, and the cellular response to radiocontrast removal for CIN remains unclear. This study aimed to explore the latent effects of iohexol in cultured [...] Read more.
Contrast-induced nephropathy (CIN) is one of the most common causes of acute kidney injury (AKI). However, management is still limited, and the cellular response to radiocontrast removal for CIN remains unclear. This study aimed to explore the latent effects of iohexol in cultured renal tubular cells with or without the removal of iohexol by medium replacement. HK2 renal tubular cells were subcultured 24 h before use in CIN experiments. Three treatment groups were established: the control, a radiocontrast (iohexol)-only group at 75 mg I/mL (I-75), and iohexol exposure for 24 h with culture medium replacement (I-75/M). Cell cycle arrest, fibrogenic mediator assays, cell viability, cell function, and cell-cycle-related protein expression were compared between groups. Iohexol induced numerous changes in HK2 renal tubular cells, such as enlarged cell shape, cell cycle arrest, increased apoptosis, and polyploidy. Iohexol inhibited the expression of cyclins, CDKs, ZO-1, and E-cadherin but conversely enhanced the expression of p21 and fibrosis-related genes, including TGF-β1, CTGF, collagen I, collagen III, and HIF-1α within 60 hr after the exposure. Except for the recovery from cell cycle arrest and cell cycle gene expression, notably, the removal of iohexol by medium replacement could not fully recover the renal tubular cells from the formation of polyploid cells, the adhesion or spreading, or the expression of fibrosis-related genes. The present study demonstrates, for the first time, that iohexol exerts latent cytotoxic effects on cultured renal tubular cells after its removal, suggesting that these irreversible cell changes may cause the insufficiency of radiocontrast reduction in CIN, which is worth investigating further. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury 2.0)
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12 pages, 1458 KiB  
Communication
CD44 Expression in Renal Tissue Is Associated with an Increase in Urinary Levels of Complement Components in Chronic Glomerulopathies
by Natalia Chebotareva, Anatoliy Vinogradov, Larisa Tsoy, Vladimir Varshavskiy, Ekaterina Stoljarevich, Anna Bugrova, Yulia Lerner, Tatyana Krasnova, Evgeniya Biryukova and Alexey S. Kononikhin
Int. J. Mol. Sci. 2023, 24(8), 7190; https://doi.org/10.3390/ijms24087190 - 13 Apr 2023
Cited by 3 | Viewed by 1934
Abstract
It is suggested that activated CD44+ cells play a profibrogenic role in the pathogenesis of active glomerulopathies. Complement activation is also involved in renal fibrogenesis. The aim of the study was to evaluate the role of the activation of CD44+ cells in the [...] Read more.
It is suggested that activated CD44+ cells play a profibrogenic role in the pathogenesis of active glomerulopathies. Complement activation is also involved in renal fibrogenesis. The aim of the study was to evaluate the role of the activation of CD44+ cells in the kidney tissue and complement components’ filtration to the urine as factors of renal tissue fibrosis in patients with glomerulopathies. In total, 60 patients with active glomerulopathies were included in our study: 29 patients with focal segmental glomerulosclerosis (FSGS), 10 patients with minimal change disease (MCD), 10 patients with membranous nephropathy (MN), and 11 patients with IgA nephropathy. The immunohistochemical peroxidase method was used to study the expression of CD44+ in kidney biopsies. Components of complement were analyzed in urine by the multiple reaction monitoring (MRM) approach using liquid chromatography. Strong CD44 expression was noted predominantly in PEC and mesangial cells (MC) in patients with FSGS, and to a lesser extent, in patients with MN and IgA nephropathy, and it was absent in patients with MCD. Expression of profibrogenic CD44+ in glomeruli correlated with the levels of proteinuria and complement C2, C3, and C9 components, and CFB and CFI in urine. The CD44+ expression scores in the renal interstitium correlated with the level of C3 and C9 components of complement in the urine and the area of tubulo-interstitial fibrosis. The strongest expression of CD44+ was found in the glomeruli (MC, PEC, and podocytes) of patients with FSGS compared with other glomerulopathies. The CD44 expression score in the glomeruli and interstitium is associated with high levels of complement components in the urine and renal fibrosis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury 2.0)
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Review

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13 pages, 571 KiB  
Review
Nephrotoxicity in the Age of Immune Checkpoint Inhibitors: Mechanisms, Diagnosis, and Management
by Krishna Moturi, Harsh Sharma and Neda Hashemi-Sadraei
Int. J. Mol. Sci. 2024, 25(1), 414; https://doi.org/10.3390/ijms25010414 - 28 Dec 2023
Cited by 5 | Viewed by 1880
Abstract
Immune checkpoint inhibitors (ICI) revolutionized cancer therapy by augmenting anti-tumor immunity via cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1/programmed death-ligand 1 (PD-1/PD-L1). However, this breakthrough is accompanied by immune-related adverse effects (irAEs), including renal complications. ICI-related nephritis involves complex mechanisms like auto-reactive [...] Read more.
Immune checkpoint inhibitors (ICI) revolutionized cancer therapy by augmenting anti-tumor immunity via cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1/programmed death-ligand 1 (PD-1/PD-L1). However, this breakthrough is accompanied by immune-related adverse effects (irAEs), including renal complications. ICI-related nephritis involves complex mechanisms like auto-reactive T cells, auto-antibodies, reactivation of drug-specific T cells, and cytokine-driven inflammation culminating in AKI. ICI-AKI typically manifests weeks to months into treatment, often with other irAEs. Timely detection relies on monitoring creatinine levels and urine characteristics. Biomarkers, like soluble interleukin-2 receptor (sIL-2R) and urine cytokine levels, provide non-invasive insights, while renal biopsy remains the gold standard for confirmation. Management of ICI-AKI requires a balance between discontinuing ICI therapy and prompt immunosuppressive intervention, typically with corticosteroids. Some cases permit ICI therapy resumption, but varying renal recovery rates highlight the importance of vigilant monitoring and effective therapy. Beyond its clinical implications, the potential of irAEs to predict positive treatment responses in certain cancers raises intriguing questions. Data on nephritis–treatment response links are limited, and ongoing research explores this complex interaction. In summary, ICI therapy’s transformative impact on cancer treatment is counterbalanced by irAEs, including nephritis. Early recognition and management are vital, with ongoing research refining diagnostic and treatment strategies. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury 2.0)
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23 pages, 1094 KiB  
Review
The Review of Current Knowledge on Neutrophil Gelatinase-Associated Lipocalin (NGAL)
by Katarzyna Romejko, Magdalena Markowska and Stanisław Niemczyk
Int. J. Mol. Sci. 2023, 24(13), 10470; https://doi.org/10.3390/ijms241310470 - 21 Jun 2023
Cited by 54 | Viewed by 7184
Abstract
Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein that is secreted mostly by immune cells such as neutrophils, macrophages, and dendritic cells. Its production is stimulated in response to inflammation. The concentrations of NGAL can be measured in plasma, urine, and biological fluids [...] Read more.
Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein that is secreted mostly by immune cells such as neutrophils, macrophages, and dendritic cells. Its production is stimulated in response to inflammation. The concentrations of NGAL can be measured in plasma, urine, and biological fluids such as peritoneal effluent. NGAL is known mainly as a biomarker of acute kidney injury and is released after tubular damage and during renal regeneration processes. NGAL is also elevated in chronic kidney disease and dialysis patients. It may play a role as a predictor of the progression of renal function decreases with complications and mortality due to kidney failure. NGAL is also useful in the diagnostic processes of cardiovascular diseases. It is highly expressed in injured heart tissue and atherosclerostic plaque; its serum concentrations correlate with the severity of heart failure and coronary artery disease. NGAL increases inflammatory states and its levels rise in arterial hypertension, obesity, diabetes, and metabolic complications such as insulin resistance, and is also involved in carcinogenesis. In this review, we present the current knowledge on NGAL and its involvement in different pathologies, especially its role in renal and cardiovascular diseases. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury 2.0)
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