International Journal of Molecular Sciences

Research

21 pages, 17074 KiB

Open AccessArticle

Expression of Autophagy Markers LC3B, LAMP2A, and GRP78 in the Human Kidney during Embryonic, Early Fetal, and Postnatal Development and Their Significance in Diabetic Kidney Disease

by Ivan Brdar, Anita Racetin, Ivo Jeličić, Katarina Vukojević, Ljiljana Vučković, Dragan Ljutić, Mirna Saraga-Babić and Natalija Filipović

Int. J. Mol. Sci. 2024, 25(17), 9152; https://doi.org/10.3390/ijms25179152 - 23 Aug 2024

Viewed by 841

Abstract

Autophagy is the primary intracellular degradation system, and it plays an important role in many biological and pathological processes. Studies of autophagy involvement in developmental processes are important for understanding various processes. Among them are fibrosis, degenerative diseases, cancer development, and metastasis formation. [...] Read more.

Autophagy is the primary intracellular degradation system, and it plays an important role in many biological and pathological processes. Studies of autophagy involvement in developmental processes are important for understanding various processes. Among them are fibrosis, degenerative diseases, cancer development, and metastasis formation. Diabetic kidney disease is one of the main causes of chronic kidney disease and end-stage renal failure. The aim of this study was to investigate the immunohistochemical expression patterns of LC3B, LAMP2A, and GRP78 during different developmental stages of early-developing human kidneys and in samples from patients with type II diabetes mellitus. During the 7/8th DW, moderate expression of LC3B and LAMP2A and strong expression of GRP78 were found in the mesonephric glomeruli and tubules. In the 9/10th DW, the expression of LC3B and LAMP2A was even more pronounced in the mesonephric tubules. LC3B, LAMP2A, and GRP78 immunoreactivity was also found in the paramesonephric and mesonephric ducts and was stronger in the 9/10th DW compared with the 7/8th DW. In addition, the expression of LC3B, LAMP2A, and GRP78 also appeared in the mesenchyme surrounding the paramesonephric duct in the 9/10th DW. In the 15/16th DW, the expression of LC3B in the glomeruli was weak, that of LAMP2A was moderate, and that of GRP78 was strong. In the tubuli, the expression of LC3B was moderate, while the expression of LAMP2A and GRP78 was strong. The strongest expression of LC3B, LAMP2A, and GRP78 was observed in the renal medullary structures, including developing blood vessels. In postnatal human kidneys, the most extensive LC3B, LAMP2A, and GRP78 expression in the cortex was found in the epithelium of the proximal convoluted tubules, with weak to moderate expression in the glomeruli. The medullary expression of LC3B was weak, but the expression of LAMP2A and GRP78 was the strongest in the medullary tubular structures. Significantly lower expression of LC3B was found in the glomeruli of the diabetic patients in comparison with the nondiabetic patients, but there was no difference in the expression of LC3B in the tubule–interstitial compartment. The expression of LAMP2A was significantly higher in the tubule–interstitial compartments of the diabetic patients in comparison with the nondiabetic patients, while its expression did not differ in the glomeruli. Extensive expression of GRP78 was found in the glomeruli and the tubule–interstitial compartments, but there was no difference in the expression between the two groups of patients. These data give us new information about the expression of LC3B, LAMP2A, and GRP78 during embryonic, fetal, and early postnatal development. The spatiotemporal expression of LC3B, LAMP2A, and GRP78 indicates the important role of autophagy during the early stages of renal development. In addition, our data suggest a disturbance in autophagy processes in the glomeruli and tubuli of diabetic kidneys as an important factor in the pathogenesis of diabetic kidney disease. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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15 pages, 3588 KiB

Open AccessArticle

Phenotypic and Genotypic Features of the FAN1 Mutation-Related Disease in a Large Hungarian Family

by Ildikó Császár, Tibor Kalmár, Zoltán Maróti, János Ávéd, Edit Szederkényi, János Zombori, Gabriella Pankotai-Bodó, Sándor Turkevi-Nagy and Béla Iványi

Int. J. Mol. Sci. 2024, 25(11), 5907; https://doi.org/10.3390/ijms25115907 - 29 May 2024

Cited by 1 | Viewed by 1033

Abstract

Pathogenic variants in the FAN1 gene lead to a systemic disease with karyomegalic interstitial nephritis (KIN) at the forefront clinically. The phenotypic–genotypic features of a FAN1 mutation-related disease involving five members of a Hungarian Caucasian family are presented. Each had adult-onset chronic kidney [...] Read more.

Pathogenic variants in the FAN1 gene lead to a systemic disease with karyomegalic interstitial nephritis (KIN) at the forefront clinically. The phenotypic–genotypic features of a FAN1 mutation-related disease involving five members of a Hungarian Caucasian family are presented. Each had adult-onset chronic kidney disease of unknown cause treated with renal replacement therapy and elevated liver enzymes. Short stature, emaciation, latte-colored skin, freckles, and a hawk-like nose in four patients, a limited intellect in two patients, and chronic restrictive lung disease in one patient completed the phenotype. Severe infections occurred in four patients. All five patients had ceased. Four patients underwent autopsy. KIN and extrarenal karyomegaly were observed histologically; the livers showed no specific abnormality. The genotyping using formalin-fixed tissue samples detected a hitherto undescribed homozygous FAN1 mutation (c.1673_1674insT/p.Met558lfs*4; exon 5) in three of these patients and a heterozygous FAN1 mutation in one patient. The reason for the heterozygosity is discussed. In addition, 56 family members consented to the screening for FAN1 mutation from which 17 individuals proved to be heterozygous carriers; a blood chemistry evaluation of their kidney and liver function did not find any abnormality. The clinical presentation of FAN1-related disease was multifaceted, and not yet described manifestations were observed besides kidney and liver disease. Mutation in this gene should be suspected in adults with small kidneys of unknown cause, elevated liver enzymes, and recurrent infections, even without a family history. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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13 pages, 1371 KiB

Open AccessArticle

Treatment with Rasburicase in Hospitalized Patients with Cardiorenal Syndrome: Old Treatment, New Scenario

by Rosa Melero, Beatriz Torroba-Sanz, Marian Goicoechea, Iago Sousa-Casasnovas, Jose María Barrio, Ana María García-Prieto, Patrocinio Rodriguez-Benitez, Xandra García-González and María Sanjurjo-Sáez

Int. J. Mol. Sci. 2024, 25(6), 3329; https://doi.org/10.3390/ijms25063329 - 15 Mar 2024

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Abstract

Cardiorenal syndrome (CRS) involves joint dysfunction of the heart and kidney. Acute forms share biochemical alterations like hyperuricaemia (HU) with tumour lysis syndrome (TLS). The mainstay treatment of acute CRS with systemic overload is diuretics, but rasburicase is used in TLS to prevent [...] Read more.

Cardiorenal syndrome (CRS) involves joint dysfunction of the heart and kidney. Acute forms share biochemical alterations like hyperuricaemia (HU) with tumour lysis syndrome (TLS). The mainstay treatment of acute CRS with systemic overload is diuretics, but rasburicase is used in TLS to prevent and treat hyperuricaemia. An observational, retrospective study was performed to assess the effectiveness and safety of a single dose of rasburicase in hospitalized patients with cardiorenal syndrome, worsening renal function and uric acid levels above 9 mg/dL. Rasburicase improved diuresis and systemic congestion in the 35 patients included. A total of 86% of patients did not need to undergo RRT, and early withdrawal was possible in the remaining five. Creatinine (Cr) decreased after treatment with rasburicase from a peak of 3.6 ± 1.27 to 1.79 ± 0.83 mg/dL, and the estimated glomerular filtration rate (eGFR) improved from 17 ± 8 to 41 ± 20 mL/min/1.73 m² (p = 0.0001). The levels of N-terminal type B Brain Natriuretic Peptide (Nt-ProBNP) and C-reactive protein (CRP) were also significantly reduced. No relevant adverse events were detected. Our results show that early treatment with a dose of rasburicase in patients with CRS and severe HU is effective to improve renal function and systemic congestion, avoiding the need for sustained extrarenal clearance, regardless of comorbidities and ventricular function. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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19 pages, 6374 KiB

Open AccessArticle

Profiling Cell Heterogeneity and Fructose Transporter Expression in the Rat Nephron by Integrating Single-Cell and Microdissected Tubule Segment Transcriptomes

by Ronghao Zhang, Darshan Aatmaram Jadhav, Najeong Kim, Benjamin Kramer and Agustin Gonzalez-Vicente

Int. J. Mol. Sci. 2024, 25(5), 3071; https://doi.org/10.3390/ijms25053071 - 6 Mar 2024

Cited by 1 | Viewed by 1855

Abstract

Single-cell RNA sequencing (scRNAseq) is a crucial tool in kidney research. These technologies cluster cells based on transcriptome similarity, irrespective of the anatomical location and order within the nephron. Thus, a transcriptome cluster may obscure the heterogeneity of the cell population within a [...] Read more.

Single-cell RNA sequencing (scRNAseq) is a crucial tool in kidney research. These technologies cluster cells based on transcriptome similarity, irrespective of the anatomical location and order within the nephron. Thus, a transcriptome cluster may obscure the heterogeneity of the cell population within a nephron segment. Elevated dietary fructose leads to salt-sensitive hypertension, in part, through fructose reabsorption in the proximal tubule (PT). However, the organization of the four known fructose transporters in apical PTs (SGLT4, SGLT5, GLUT5, and NaGLT1) remains poorly understood. We hypothesized that cells within each subsegment of the proximal tubule exhibit complex, heterogeneous fructose transporter expression patterns. To test this hypothesis, we analyzed rat kidney transcriptomes and proteomes from publicly available scRNAseq and tubule microdissection databases. We found that microdissected PT-S1 segments consist of 81% ± 12% cells with scRNAseq-derived transcriptional characteristics of S1, whereas PT-S2 express a mixture of 18% ± 9% S1, 58% ± 8% S2, and 19% ± 5% S3 transcripts, and PT-S3 consists of 75% ± 9% S3 transcripts. The expression of all four fructose transporters was detectable in all three PT segments, but key fructose transporters SGLT5 and GLUT5 progressively increased from S1 to S3, and both were significantly upregulated in S3 vs. S1/S2 (Slc5a10: 1.9 log2FC, p < 1 × 10⁻²⁹⁹; Scl2a5: 1.4 log2FC, p < 4 × 10⁻¹⁰⁵). A similar distribution was found in human kidneys. These data suggest that S3 is the primary site of fructose reabsorption in both humans and rats. Finally, because of the multiple scRNAseq transcriptional phenotypes found in each segment, our findings also imply that anatomical labels applied to scRNAseq clusters may be misleading. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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16 pages, 3810 KiB

Open AccessArticle

Increased Circulating Irisin Levels in Kidney Transplant Patients: Is There a Connection with Glycaemic Control?

by Beata Bzoma, Agnieszka Kuchta, Kornelia Sałaga-Zaleska, Aleksandra Krzesińska, Gabriela Chyła-Danił, Maciej Jankowski and Alicja Dębska-Ślizień

Int. J. Mol. Sci. 2024, 25(5), 2926; https://doi.org/10.3390/ijms25052926 - 2 Mar 2024

Viewed by 895

Abstract

Irisin is a myokine with potential effects on glucose metabolism and the development of diabetes in humans. We analysed irisin serum levels (ISL) in 47 patients without diabetes before and 1, 2, 3, 4 and 5 weeks after kidney transplantation (KTx). All measurements [...] Read more.

Irisin is a myokine with potential effects on glucose metabolism and the development of diabetes in humans. We analysed irisin serum levels (ISL) in 47 patients without diabetes before and 1, 2, 3, 4 and 5 weeks after kidney transplantation (KTx). All measurements of irisin before KTx levels were lower than 25 ng/mL (median 8.4 ng/mL). We found an outstanding increase in ISL measured after KTx, reaching more than 1000 times in 44% of patients (HIL—high irisin level group). The increase appeared at the first measurement (one week after KTx). Factors connected to the large growth of ISL were, i.e., BMI > 30 (p = 0.04) and subsequent KTx—second and third (p < 0.001). The global mean blood glucose level during the first two weeks after KTx was significantly lower in the HIL group (p = 0.002), the same as the day-by-day analysed mean fasting and postprandial serum glucose in the first days after KTx. In 12 months of observation, diabetes requiring insulin therapy occurred in the HIL group at a rate of 19%, while in the rest of the patients, the rate was 27%, p = 0.526. Irisin levels increase significantly in some patients after kidney transplantation, accompanied by lower blood glucose levels in the early post-transplant period. Whether an increase in irisin levels results in better glycaemic control remains questionable and requires further research, as well as the relationship between irisin levels and the occurrence of PTDM. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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16 pages, 3280 KiB

Open AccessArticle

Monocytes as Targets for Immunomodulation by Regional Citrate Anticoagulation

by Giovana Seno Di Marco, Achmet Imam Chasan, Göran Ramin Boeckel, Katrin Beul, Hermann Pavenstädt, Johannes Roth and Marcus Brand

Int. J. Mol. Sci. 2024, 25(5), 2900; https://doi.org/10.3390/ijms25052900 - 1 Mar 2024

Viewed by 1323

Abstract

Immune alterations in end-stage renal patients receiving hemodialysis are complex and predispose patients to infections. Anticoagulation may also play an immunomodulatory role in addition to the accumulation of uremic toxins and the effects of the dialysis procedure. Accordingly, it has been recently shown [...] Read more.

Immune alterations in end-stage renal patients receiving hemodialysis are complex and predispose patients to infections. Anticoagulation may also play an immunomodulatory role in addition to the accumulation of uremic toxins and the effects of the dialysis procedure. Accordingly, it has been recently shown that the infection rate increases in patients under regional citrate anticoagulation (RCA) compared with systemic heparin anticoagulation (SHA). We hypothesized that RCA affects the immune status of hemodialysis patients by targeting monocytes. In a cohort of 38 end-stage renal patients undergoing hemodialysis, we demonstrated that whole blood monocytes of patients receiving RCA—but not SHA—failed to upregulate surface activation markers, like human leukocyte antigen class II (HLA-DR), after stressful insults, indicating a state of deactivation during and immediately after dialysis. Additionally, RNA sequencing (RNA-seq) data and gene set enrichment analysis of pre-dialysis monocytes evidenced a great and complex difference between the groups given that, in the RCA group, monocytes displayed a dramatic transcriptional change with increased expression of genes related to the cell cycle regulation, cellular metabolism, and cytokine signaling, compatible with the reprogramming of the immune response. Transcriptomic changes in pre-dialysis monocytes signalize the lasting nature of the RCA-related effects, suggesting that monocytes are affected even beyond the dialysis session. Furthermore, these findings demonstrate that RCA—but not SHA—impairs the response of monocytes to activation stimuli and alters the immune status of these patients with potential clinical implications. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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13 pages, 1728 KiB

Open AccessArticle

Inflammation in Hypervolemic Hemodialysis Patients: The Roles of RelB and Caspase-4

by Christof Ulrich, Zeynep Canim, Eva Herberger, Matthias Girndt and Roman Fiedler

Int. J. Mol. Sci. 2023, 24(24), 17550; https://doi.org/10.3390/ijms242417550 - 16 Dec 2023

Cited by 1 | Viewed by 1159

Abstract

Hypervolemia is associated with inflammation in hemodialysis (HD) patients. How hypervolemia triggers inflammation is not entirely known. We initiated a cross-sectional study enrolling 40 hemodialysis patients who were categorized into normovolemic (N; 23) and hypervolemic (H; 17) groups by bioimpedance measurement. A caspase [...] Read more.

Hypervolemia is associated with inflammation in hemodialysis (HD) patients. How hypervolemia triggers inflammation is not entirely known. We initiated a cross-sectional study enrolling 40 hemodialysis patients who were categorized into normovolemic (N; 23) and hypervolemic (H; 17) groups by bioimpedance measurement. A caspase activity assay in combination with a specific caspase-4 inhibitor was used to detect caspase-4 activity in isolated peripheral blood mononuclear cells (PBMCs). Transcription factors RelA (pS529) and RelB (pS552) were analyzed by phospho-flow cytometry. Serum endotoxins were detected by an amebocyte lysate-based assay, and IL-6 (interleukin-6) and TNF-α (Tumor necrosis factor-α) gene expression were detected using the ELISA technique. Hypervolemic patients were older, more frequently had diabetes and showed increased CRP and IL-6 levels. Caspase-4 activity, which is linked to intracellular endotoxin detection, was significantly elevated in H patients. While the frequency of RelA-expressing immune cells and the expression density in these cells did not differ, the monocytic frequency of cells positively stained for RelB (pS552) was significantly decreased in H patients. Increased caspase-4 activity in H patients may indicate a cause of inflammation in H patients. The post-translational modification of RelB (pS552) is linked to downregulation of NF-kB activity and may indicate the resolution of inflammation, which is more distinct in N patients compared to H patients. Therefore, both higher inflammatory loads and lower inflammatory resolution capacities are characteristics of H patients. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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11 pages, 2454 KiB

Open AccessArticle

Proenkephalin Levels and Its Determinants in Patients with End-Stage Kidney Disease Treated with Hemodialysis and Peritoneal Dialysis

by Wiktoria Grycuk, Zuzanna Jakubowska and Jolanta Małyszko

Int. J. Mol. Sci. 2023, 24(19), 15015; https://doi.org/10.3390/ijms241915015 - 9 Oct 2023

Cited by 1 | Viewed by 1267

Abstract

Recently, proenkephalin A (PENK A) has been shown to reflect glomerular dysfunction and to predict new-onset acute kidney injury and heart failure. While previous studies have investigated PENK A as a biomarker in individuals with preserved renal function, PENK A concentration in patients [...] Read more.

Recently, proenkephalin A (PENK A) has been shown to reflect glomerular dysfunction and to predict new-onset acute kidney injury and heart failure. While previous studies have investigated PENK A as a biomarker in individuals with preserved renal function, PENK A concentration in patients with end-stage kidney disease (ESKD) was not investigated. Plasma PENK A concentration was assessed in 88 patients with ESKD treated with hemodialysis (HD) or peritoneal dialysis (PD), and its associations with kidney function and heart failure indicators were investigated. In HD patients, the difference in PENK A levels before and after hemodialysis, was measured and further assessed for an association with the type of HD membrane used. PENK A levels did not differ significantly between HD and PD patients. In HD patients, the median PENK A concentration was significantly higher before than after hemodialysis (1.368 vs. 2.061, p = 0.003). No correlation was found between PENK A level and urea (p = 0.192), eGFR (p = 0.922), dialysis vintage (p = 0.637), and residual urine output (p = 0.784). Heart failure (p = 0.961), EF (p = 0.361), and NT-proBNP (p = 0.949) were not associated with increased PENK A concentration. PENK A does not reflect renal function and cardiac status in patients with ESKD. Further research is required to establish the clinical utility of the new biomarker in patients with impaired kidney function. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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14 pages, 3707 KiB

Open AccessArticle

Nanoparticle Tracking Analysis of Urinary Extracellular Vesicle Proteins as a New Challenge in Laboratory Medicine

by Kornelia Sałaga-Zaleska, Agnieszka Kuchta, Beata Bzoma, Gabriela Chyła-Danił, Anna Safianowska, Agata Płoska, Leszek Kalinowski, Alicja Dębska-Ślizień and Maciej Jankowski

Int. J. Mol. Sci. 2023, 24(15), 12228; https://doi.org/10.3390/ijms241512228 - 31 Jul 2023

Cited by 4 | Viewed by 1943

Abstract

Urinary extracellular vesicle (uEV) proteins may be used as specific markers of kidney damage in various pathophysiological conditions. The nanoparticle-tracking analysis (NTA) appears to be the most useful method for the analysis of uEVs due to its ability to analyze particles below 300 [...] Read more.

Urinary extracellular vesicle (uEV) proteins may be used as specific markers of kidney damage in various pathophysiological conditions. The nanoparticle-tracking analysis (NTA) appears to be the most useful method for the analysis of uEVs due to its ability to analyze particles below 300 nm. The NTA method has been used to measure the size and concentration of uEVs and also allows for a deeper analysis of uEVs based on their protein composition using fluorescence measurements. However, despite much interest in the clinical application of uEVs, their analysis using the NTA method is poorly described and requires meticulous sample preparation, experimental adjustment of instrument settings, and above all, an understanding of the limitations of the method. In the present work, we demonstrate the usefulness of an NTA. We also present problems encountered during analysis with possible solutions: the choice of sample dilution, the method of the presentation and comparison of results, photobleaching, and the adjustment of instrument settings for a specific analysis. We show that the NTA method appears to be a promising method for the determination of uEVs. However, it is important to be aware of potential problems that may affect the results. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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17 pages, 2842 KiB

Open AccessArticle

Unveiling Angiotensin II and Losartan-Induced Gene Regulatory Networks Using Human Urine-Derived Podocytes

by Chantelle Thimm, Lars Erichsen, Wasco Wruck and James Adjaye

Int. J. Mol. Sci. 2023, 24(13), 10551; https://doi.org/10.3390/ijms241310551 - 23 Jun 2023

Cited by 2 | Viewed by 2101

Abstract

Podocytes are highly specialized cells that play a pivotal role in the blood filtration process in the glomeruli of the kidney, and their dysfunction leads to renal diseases. For this reason, the study and application of this cell type is of great importance [...] Read more.

Podocytes are highly specialized cells that play a pivotal role in the blood filtration process in the glomeruli of the kidney, and their dysfunction leads to renal diseases. For this reason, the study and application of this cell type is of great importance in the field of regenerative medicine. Hypertension is mainly regulated by the renin–angiotensin–aldosterone system (RAAS), with its main mediator being angiotensin II (ANG II). Elevated ANG II levels lead to a pro-fibrotic, inflammatory, and hypertrophic milieu that induces apoptosis in podocytes. The activation of RAAS is critical for the pathogenesis of podocyte injury; as such, to prevent podocyte damage, patients with hypertension are administered drugs that modulate RAAS signaling. A prime example is the orally active, non-peptide, selective angiotensin-II-type I receptor (AGTR1) blocker losartan. Here, we demonstrate that SIX2-positive urine-derived renal progenitor cells (UdRPCs) and their immortalized counterpart (UM51-hTERT) can be directly differentiated into mature podocytes. These podocytes show activation of RAAS after stimulation with ANG II, resulting in ANG II-dependent upregulation of the expression of the angiotensin-II-type I receptor, AGTR1, and the downregulated expression of the angiotensin-II-type II receptor 2 (AGTR2). The stimulation of podocytes with losartan counteracts ANG II-dependent changes, resulting in a dependent favoring of the specific receptor from AGTR1 to AGTR2. Transcriptome analysis revealed 94 losartan-induced genes associated with diverse biological processes and pathways such as vascular smooth muscle contraction, the oxytocin signaling pathway, renin secretion, and ECM-receptor interaction. Co-stimulation with losartan and ANG II induced the exclusive expression of 106 genes associated with DNA methylation or demethylation, cell differentiation, the developmental process, response to muscle stretch, and calcium ion transmembrane transport. These findings highlight the usefulness of UdRPC-derived podocytes in studying the RAAS pathway and nephrotoxicity in various kidney diseases. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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Review

Jump to: Research, Other

14 pages, 1461 KiB

Open AccessReview

GDF15, an Emerging Player in Renal Physiology and Pathophysiology

by Samia Lasaad and Gilles Crambert

Int. J. Mol. Sci. 2024, 25(11), 5956; https://doi.org/10.3390/ijms25115956 - 29 May 2024

Cited by 1 | Viewed by 1272

Abstract

These last years, the growth factor GDF15 has emerged as a key element in many different biological processes. It has been established as being produced in response to many pathological states and is now referred to as a stress-related hormone. Regarding kidney functions, [...] Read more.

These last years, the growth factor GDF15 has emerged as a key element in many different biological processes. It has been established as being produced in response to many pathological states and is now referred to as a stress-related hormone. Regarding kidney functions, GDF15 has been involved in different pathologies such as chronic kidney disease, diabetic nephropathy, renal cancer, and so on. Interestingly, recent studies also revealed a role of GDF15 in the renal homeostatic mechanisms allowing to maintain constant, as far as possible, the plasma parameters such as pH and K⁺ values. In this review, we recapitulate the role of GDF15 in physiological and pathological context by focusing our interest on its renal effect. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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21 pages, 1502 KiB

Open AccessReview

Iron Metabolism and Inflammatory Mediators in Patients with Renal Dysfunction

by Tomomi Matsuoka, Masanori Abe and Hiroki Kobayashi

Int. J. Mol. Sci. 2024, 25(7), 3745; https://doi.org/10.3390/ijms25073745 - 27 Mar 2024

Cited by 1 | Viewed by 2272

Abstract

Chronic kidney disease (CKD) affects around 850 million people worldwide, posing significant challenges in healthcare due to complications like renal anemia, end-stage kidney disease, and cardiovascular diseases. This review focuses on the intricate interplay between iron metabolism, inflammation, and renal dysfunction in CKD. [...] Read more.

Chronic kidney disease (CKD) affects around 850 million people worldwide, posing significant challenges in healthcare due to complications like renal anemia, end-stage kidney disease, and cardiovascular diseases. This review focuses on the intricate interplay between iron metabolism, inflammation, and renal dysfunction in CKD. Renal anemia, prevalent in CKD, arises primarily from diminished erythropoietin (EPO) production and iron dysregulation, which worsens with disease progression. Functional and absolute iron deficiencies due to impaired absorption and chronic inflammation are key factors exacerbating erythropoiesis. A notable aspect of CKD is the accumulation of uremic toxins, such as indoxyl sulfate (IS), which hinder iron metabolism and worsen anemia. These toxins directly affect renal EPO synthesis and contribute to renal hypoxia, thus playing a critical role in the pathophysiology of renal anemia. Inflammatory cytokines, especially TNF-α and IL-6, further exacerbate CKD progression and disrupt iron homeostasis, thereby influencing anemia severity. Treatment approaches have evolved to address both iron and EPO deficiencies, with emerging therapies targeting hepcidin and employing hypoxia-inducible factor (HIF) stabilizers showing potential. This review underscores the importance of integrated treatment strategies in CKD, focusing on the complex relationship between iron metabolism, inflammation, and renal dysfunction to improve patient outcomes. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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13 pages, 1151 KiB

Open AccessReview

Transcription Factors in the Pathogenesis of Lupus Nephritis and Their Targeted Therapy

by Kasey M. Shao and Wen-Hai Shao

Int. J. Mol. Sci. 2024, 25(2), 1084; https://doi.org/10.3390/ijms25021084 - 16 Jan 2024

Viewed by 1819

Abstract

Systemic lupus erythematosus (SLE) is a prototype inflammatory autoimmune disease, characterized by breakdown of immunotolerance to self-antigens. Renal involvement, known as lupus nephritis (LN), is one of the leading causes of morbidity and a significant contributor to mortality in SLE. Despite current pathophysiological [...] Read more.

Systemic lupus erythematosus (SLE) is a prototype inflammatory autoimmune disease, characterized by breakdown of immunotolerance to self-antigens. Renal involvement, known as lupus nephritis (LN), is one of the leading causes of morbidity and a significant contributor to mortality in SLE. Despite current pathophysiological advances, further studies are needed to fully understand complex mechanisms underlying the development and progression of LN. Transcription factors (TFs) are proteins that regulate the expression of genes and play a crucial role in the development and progression of LN. The mechanisms of TF promoting or inhibiting gene expression are complex, and studies have just begun to reveal the pathological roles of TFs in LN. Understanding TFs in the pathogenesis of LN can provide valuable insights into this disease’s mechanisms and potentially lead to the development of targeted therapies for its management. This review will focus on recent findings on TFs in the pathogenesis of LN and newly developed TF-targeted therapy in renal inflammation. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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15 pages, 1385 KiB

Open AccessReview

Spice Up Your Kidney: A Review on the Effects of Capsaicin in Renal Physiology and Disease

by Michela Musolino, Mario D’Agostino, Mariateresa Zicarelli, Michele Andreucci, Giuseppe Coppolino and Davide Bolignano

Int. J. Mol. Sci. 2024, 25(2), 791; https://doi.org/10.3390/ijms25020791 - 8 Jan 2024

Cited by 3 | Viewed by 3361

Abstract

Capsaicin, the organic compound which attributes the spicy flavor and taste of red peppers and chili peppers, has been extensively studied for centuries as a potential natural remedy for the treatment of several illnesses. Indeed, this compound exerts well-known systemic pleiotropic effects and [...] Read more.

Capsaicin, the organic compound which attributes the spicy flavor and taste of red peppers and chili peppers, has been extensively studied for centuries as a potential natural remedy for the treatment of several illnesses. Indeed, this compound exerts well-known systemic pleiotropic effects and may thus bring important benefits against various pathological conditions like neuropathic pain, rhinitis, itching, or chronic inflammation. Yet, little is known about the possible biological activity of capsaicin at the kidney level, as this aspect has only been addressed by sparse experimental investigations. In this paper, we aimed to review the available evidence focusing specifically on the effects of capsaicin on renal physiology, as well as its potential benefits for the treatment of various kidney disorders. Capsaicin may indeed modulate various aspects of renal function and renal nervous activity. On the other hand, the observed experimental benefits in preventing acute kidney injury, slowing down the progression of diabetic and chronic kidney disease, ameliorating hypertension, and even delaying renal cancer growth may set the stage for future human trials of capsaicin administration as an adjuvant or preventive therapy for different, difficult-to-treat renal diseases. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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34 pages, 1065 KiB

Open AccessReview

Hepatorenal Syndrome—Novel Insights into Diagnostics and Treatment

by Krzysztof Badura, Weronika Frąk, Joanna Hajdys, Gabriela Majchrowicz, Ewelina Młynarska, Jacek Rysz and Beata Franczyk

Int. J. Mol. Sci. 2023, 24(24), 17469; https://doi.org/10.3390/ijms242417469 - 14 Dec 2023

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Abstract

Hepatorenal syndrome (HRS) is a disorder associated with cirrhosis and renal impairment, with portal hypertension as its major underlying cause. Moreover, HRS is the third most common cause of acute kidney injury, thus creating a major public health concern. This review summarizes the [...] Read more.

Hepatorenal syndrome (HRS) is a disorder associated with cirrhosis and renal impairment, with portal hypertension as its major underlying cause. Moreover, HRS is the third most common cause of acute kidney injury, thus creating a major public health concern. This review summarizes the available information on the pathophysiological implications of HRS. We discuss pathogenesis associated with HRS. Mechanisms such as dysfunction of the circulatory system, bacterial infection, inflammation, impaired renal autoregulation, circulatory, and others, which have been identified as critical pathways for development of HRS, have become easier to diagnose in recent years. Additionally, relatively recently, renal dysfunction biomarkers have been found indicating renal injury, which are involved in the pathophysiology of HRS. This review also summarizes the available information on the management of HRS, focusing on vasoconstrictive drugs, renal replacement therapy, and liver transplant together with currently being investigated novel therapies. Analyzing new discoveries for the underlying causes of this condition assists the general research to improve understanding of the mechanism of pathophysiology and thus prevention of HRS. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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13 pages, 291 KiB

Open AccessReview

The Role of Urinary NGAL in the Management of Primary Vesicoureteral Reflux in Children

by Cristina Gavrilovici, Cristian Petru Dusa, Codruta Iliescu Halitchi, Vasile Valeriu Lupu, Elena Lia Spoiala, Roxana Alexandra Bogos, Adriana Mocanu, Mihai Gafencu, Ancuta Lupu, Cristina Stoica and Iuliana Magdalena Starcea

Int. J. Mol. Sci. 2023, 24(9), 7904; https://doi.org/10.3390/ijms24097904 - 26 Apr 2023

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Abstract

Vesicoureteral reflux (VUR) is the most frequent congenital urinary tract malformation and an important risk factor for urinary tract infections (UTIs). Up to 50% of children with VUR may develop reflux nephropathy (RN), and the diagnosis and monitoring of renal scars are invasive [...] Read more.

Vesicoureteral reflux (VUR) is the most frequent congenital urinary tract malformation and an important risk factor for urinary tract infections (UTIs). Up to 50% of children with VUR may develop reflux nephropathy (RN), and the diagnosis and monitoring of renal scars are invasive and costly procedures, so it is paramount to find a non-invasive and accurate method to predict the risk of renal damage. Neutrophil gelatinase-associated lipocalin (NGAL) has already proven to be a good predictive biomarker in acute kidney injuries, but there are few studies that have investigated the role of NGAL in primary VUR in children. Our aim is to review the predictive value of urine NGAL (uNGAL) as a non-invasive biomarker of RN in children with primary VUR, as well as its ability to predict the evolution of chronic kidney disease (CKD). Based on our analysis of the available original studies, uNGAL can be an accurate and reliable biomarker of RN and its progression to CKD. Some studies suggested a good correlation between VUR severity and uNGAL levels, but other studies found no significant correlation. The relationship between VUR severity and uNGAL levels is likely complex and influenced by factors such as UTIs, the timing of the urine sample collection, and the age and overall health of the patient. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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12 pages, 1318 KiB

Open AccessCase Report

A Rare De Novo Mutation in the TRIM8 Gene in a 17-Year-Old Boy with Steroid-Resistant Nephrotic Syndrome: Case Report

by Marta Badeńska, Małgorzata Pac, Andrzej Badeński, Karolina Rutkowska, Justyna Czubilińska-Łada, Rafał Płoski, Nadezda Bohynikova and Maria Szczepańska

Int. J. Mol. Sci. 2024, 25(8), 4486; https://doi.org/10.3390/ijms25084486 - 19 Apr 2024

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Abstract

Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. Treatment with steroids is usually successful; however, in a small percentage of patients, steroid resistance is observed. The most frequent histologic kidney feature of steroid-resistant nephrotic syndrome (SRNS) is focal segmental [...] Read more.

Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. Treatment with steroids is usually successful; however, in a small percentage of patients, steroid resistance is observed. The most frequent histologic kidney feature of steroid-resistant nephrotic syndrome (SRNS) is focal segmental glomerulosclerosis (FSGS). Genetic testing has become a valuable diagnostic tool in defining the etiology of SRNS, leading to the identification of a genetic cause. The TRIM8 gene is expressed in various tissues, including kidney cells and the central nervous system (CNS). An association between a mutation in the TRIM8 gene and an early onset of FSGS has been proposed but is not well described. We present a 17-year-old boy with epilepsy, early mild developmental delay, a low IgG serum level, and proteinuria, secondary to FSGS. A Next-Generation Sequencing (NGS)-based analysis revealed a heterozygous de novo pathogenic variant in the TRIM8 gene (c.1200C>G, p.Tyr400Ter). TRIM8 gene sequencing should be considered in individuals with early onset of FSGS, particularly accompanied by symptoms of cortical dysfunction, such as epilepsy and intellectual disability. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors 2.0)

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