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Kidney360 Oct 2023Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1-NF (erythroid-derived 2)–like 2 pathway increases GFR without an appreciable...
KEY POINTS
Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1-NF (erythroid-derived 2)–like 2 pathway increases GFR without an appreciable increase in intraglomerular pressure. Kelch-like ECH-associated protein 1-NF (erythroid-derived 2)–like 2 pathway regulates GFR through changes in filtration area by modulating calcium dynamics and contractility in glomerular cells.
BACKGROUND
Literature data suggest that the activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF (erythroid-derived 2)–like 2 (Nrf2) pathway increases GFR in patients with type 2 diabetes and CKD. However, the mechanisms whereby the Keap1-Nrf2 pathway regulates GFR are unknown.
METHODS
Various renal physiological parameters were assessed in C57BL/6 mice (wild-type), -deficient mice, and -activated knockdown mice. In addition, these parameters were assessed after the administration of receptor targeting agent (RTA) dh404 (CDDO‐dhTFEA), an Nrf2 activator.
RESULTS
Pharmacologic and genetic - activation increased renal blood flow ( < 0.05), glomerular volume ( < 0.05), and GFR ( < 0.05) but did not alter the afferent-to-efferent arteriolar diameter ratio or glomerular permeability. Calcium influx into the podocytes through transient receptor potential canonical (TRPC) channels in response to HO was suppressed by Keap1-Nrf2 activation and TRPCs inhibition. Treatment with a TRPC6 and TRPC5 inhibitors increased single-nephron GFR in wild-type mice.
CONCLUSIONS
In conclusion, the Keap1-Nrf2 pathway regulates GFR through changes in ultrafiltration by modulating redox-sensitive intracellular calcium signaling and cellular contractility, mediated through TRPC activity, in glomerular cells, particularly the podocytes.
Topics: Cell Line, Tumor; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Signal Transduction; Animals; Mice
PubMed: 37265366
DOI: 10.34067/KID.0000000000000171 -
Wiener Klinische Wochenschrift Aug 2023The histopathological term focal-segmental glomerulosclerosis comprises different pathogenic processes with the unifying features of a high proteinuria and the...
The histopathological term focal-segmental glomerulosclerosis comprises different pathogenic processes with the unifying features of a high proteinuria and the name-giving glomerular lesion pattern seen on light microscopy. A differentiation according to the underlying cause into primary, secondary and genetic forms is therefore of utmost importance. The pathogenesis of primary focal-segmental glomerulosclerosis remains unknown but, like minimal-change disease, an autoimmune-mediated process leading to podocyte damage is assumed. Consequently, the unifying term "podocytopathy" is increasingly being used for both entities. Supportive treatment measures to preserve kidney function are important in all subtypes. In contrast, immunosuppressive treatment is only indicated in primary focal-segmental glomerulosclerosis. Steroid-dependence, steroid-resistance and frequently relapsing disease often complicate disease management and necessitate alternative treatment strategies. Here, the Austrian Society of Nephrology (ÖGN) provides consensus recommendations on how to best diagnose and manage patients with focal-segmental glomerulosclerosis.
Topics: Humans; Glomerulosclerosis, Focal Segmental; Austria; Consensus; Disease Management
PubMed: 37728649
DOI: 10.1007/s00508-023-02260-x -
Cell Communication and Signaling : CCS Feb 2024Sirtuins, which are NAD-dependent class III histone deacetylases, are involved in various biological processes, including DNA damage repair, immune inflammation,... (Review)
Review
Sirtuins, which are NAD-dependent class III histone deacetylases, are involved in various biological processes, including DNA damage repair, immune inflammation, oxidative stress, mitochondrial homeostasis, autophagy, and apoptosis. Sirtuins are essential regulators of cellular function and organismal health. Increasing evidence suggests that the development of age-related diseases, including kidney diseases, is associated with aberrant expression of sirtuins, and that regulation of sirtuins expression and activity can effectively improve kidney function and delay the progression of kidney disease. In this review, we summarise current studies highlighting the role of sirtuins in renal diseases. First, we discuss sirtuin family members and their main mechanisms of action. We then outline the possible roles of sirtuins in various cell types in kidney diseases. Finally, we summarise the compounds that activate or inhibit sirtuin activity and that consequently ameliorate renal diseases. In conclusion, targeted modulation of sirtuins is a potential therapeutic strategy for kidney diseases. Video Abstract.
Topics: Humans; Sirtuins; Kidney Diseases; Oxidative Stress; DNA Repair
PubMed: 38347622
DOI: 10.1186/s12964-023-01442-4 -
Journal of Cardiovascular Pharmacology Dec 2023The progression of chronic kidney disease results from the accumulation of extracellular matrix leading to end-stage renal disease. We previously demonstrated that a...
The progression of chronic kidney disease results from the accumulation of extracellular matrix leading to end-stage renal disease. We previously demonstrated that a broad-spectrum matrix metalloproteinase (MMP) inhibitor reduced renal injury in rat models of hypertension and diabetes. However, the isoforms and mechanisms involved are unclear. This study examined the role of MMP2 during the development of proteinuria and renal injury after induction of hypertension or diabetes in Dahl salt-sensitive (SS) and MMP2 knockout (KO) rats. Mean arterial pressure rose from 115 ± 2 to 145 ± 2 mm Hg and 116 ± 1 to 152 ± 3 mm Hg in MMP2 KO and SS rats fed a high-salt (8% NaCl) diet for 3 weeks. The degree of proteinuria, glomerular injury, renal fibrosis, and podocyte loss was lower in MMP2 KO rats than in SS rats. Blood glucose and HbA1c levels, and mean arterial pressure rose to the same extent in streptozotocin-treated SS and MMP2 KO rats. However, the degree of proteinuria, glomerulosclerosis, renal fibrosis, renal hypertrophy, glomerular permeability to albumin, and the renal expression of MMP2 and TGFβ1 were significantly reduced in MMP2 KO rats. Glomerular filtration rate fell by 33% after 12 weeks of diabetes in streptozotocin-treated SS rats compared with time-control rats, but glomerular filtration rate only fell by 12% in MMP2 KO rats. These results indicate that activation of MMP2 plays an essential role in the pathogenesis of hypertensive and diabetic nephropathy and suggests that an MMP2 inhibitor might slow the progression of chronic kidney disease.
Topics: Rats; Animals; Diabetic Nephropathies; Matrix Metalloproteinase 2; Streptozocin; Rats, Inbred Dahl; Hypertension; Kidney; Proteinuria; Renal Insufficiency, Chronic; Fibrosis; Blood Pressure; Sodium Chloride, Dietary; Diabetes Mellitus
PubMed: 37643020
DOI: 10.1097/FJC.0000000000001473 -
Advanced Science (Weinheim,... Mar 2024Podocytes are particularly sensitive to lipid accumulation, which has recently emerged as a crucial pathological process in the progression of proteinuric kidney...
Podocytes are particularly sensitive to lipid accumulation, which has recently emerged as a crucial pathological process in the progression of proteinuric kidney diseases like diabetic kidney disease and focal segmental glomerulosclerosis. However, the underlying mechanism remains unclear. Here, podocytes predominantly expressed protein dedicator of cytokinesis 5 (Dock5) is screened to be critically related to podocyte lipid lipotoxicity. Its expression is reduced in both proteinuric kidney disease patients and mouse models. Podocyte-specific deficiency of Dock5 exacerbated podocyte injury and glomeruli pathology in proteinuric kidney disease, which is mainly through modulating fatty acid uptake by the liver X receptor α (LXRα)/scavenger receptor class B (CD36) signaling pathway. Specifically, Dock5 deficiency enhanced CD36-mediated fatty acid uptake of podocytes via upregulating LXRα in an m A-dependent way. Moreover, the rescue of Dock5 expression ameliorated podocyte injury and proteinuric kidney disease. Thus, the findings suggest that Dock5 deficiency is a critical contributor to podocyte lipotoxicity and may serve as a promising therapeutic target in proteinuric kidney diseases.
Topics: Mice; Animals; Humans; Podocytes; Lipid Metabolism; Kidney Diseases; Fatty Acids; Lipids; Guanine Nucleotide Exchange Factors
PubMed: 38161229
DOI: 10.1002/advs.202306365 -
Journal of Nanobiotechnology Oct 2023Primary nephrotic syndrome (PNS) is characterized by edema, heavy proteinuria, hypoalbuminemia and hyperlipidemia. Moreover, podocyte injury is the key pathological...
BACKGROUND
Primary nephrotic syndrome (PNS) is characterized by edema, heavy proteinuria, hypoalbuminemia and hyperlipidemia. Moreover, podocyte injury is the key pathological change of PNS. Even though the pathophysiological etiology of PNS has not been fully understood, the production of excessive reactive oxygen species (ROS) plays an important role in the development and progression of the disease. Glucocorticoids are the first-line medications for patients with PNS, but their clinical use is hampered by dose-dependent side effects. Herein, we accelerated the rate of conversion from Ce to Ce by doping Zr in ceria-zirconia nanomedicines to treat the PNS rat model by removal of ROS.
RESULTS
The engineered CeZrO (7CZ) nanomedicines significantly improved the ROS scavenging ability of podocytes at a very low dose, enabling effective inhibition of podocyte apoptosis and actin cytoskeleton depolymerization induced by adriamycin (ADR). Accordingly, podocyte injury was effectively alleviated in rat models of ADR-induced nephrotic syndrome, as confirmed by serum tests and renal tissue staining. Moreover, the mRNA sequencing assay revealed the protective molecular signaling pathways of 7CZ nanomedicines in podocytes.
CONCLUSION
7CZ nanomedicines were highly effective in protecting against ADR-induced podocyte injury in vitro and in vivo at a very low concentration.
Topics: Humans; Rats; Animals; Nephrotic Syndrome; Doxorubicin; Podocytes; Antioxidants; Reactive Oxygen Species; Nanomedicine
PubMed: 37858242
DOI: 10.1186/s12951-023-02136-2 -
Frontiers in Immunology 2023Nephrotic syndrome (NS) is a relatively rare and serious presentation of IgA nephropathy (IgAN) (NS-IgAN). Previous research has suggested that the pathogenesis of...
Nephrotic syndrome (NS) is a relatively rare and serious presentation of IgA nephropathy (IgAN) (NS-IgAN). Previous research has suggested that the pathogenesis of NS-IgAN may involve circulating immune imbalance and kidney injury; however, this has yet to be fully elucidated. To investigate the cellular and molecular status of NS-IgAN, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) and kidney cells from pediatric patients diagnosed with NS-IgAN by renal biopsy. Consistently, the proportion of intermediate monocytes (IMs) in NS-IgAN patients was higher than in healthy controls. Furthermore, flow cytometry confirmed that IMs were significantly increased in pediatric patients with NS. The characteristic expression of and MHC class II molecules and an increase in oxidative phosphorylation may be important features of IMs in NS-IgAN. Notably, we found that the expression level of was significantly increased in the CMs, IMs, and NCMs of patients with NS-IgAN. This may be related to kidney injury. Regulatory T cells (Tregs) are classified into two subsets of cells: Treg1 ( , , and ) and Treg2 ( , , and ). We found that the levels of Treg2 cells expressed significant levels of and , which may be related to the recovery of kidney injury. The state of NS in patients was closely related to podocyte injury. The expression levels of , , and genes related to epithelial-mesenchymal transition were significantly increased in podocytes from NS-IgAN patients. These represent key features of podocyte injury. Our analysis suggests that is significantly downregulated following injury and may represent a new marker for podocytes. In this study, we systematically analyzed molecular events in the circulatory system and kidney tissue of pediatric patients with NS-IgAN, which provides new insights for targeted therapy in the future.
Topics: Humans; Child; Glomerulonephritis, IGA; Nephrotic Syndrome; Leukocytes, Mononuclear; Receptors, CCR7; Kidney; HLA-DR Antigens
PubMed: 37908345
DOI: 10.3389/fimmu.2023.1231937 -
Kidney Research and Clinical Practice May 2024Podocytes are involved in maintaining kidney function and are a major focus of research on diabetic kidney disease (DKD). Urinary biomarkers derived from podocyte...
Podocytes are involved in maintaining kidney function and are a major focus of research on diabetic kidney disease (DKD). Urinary biomarkers derived from podocyte fragments and molecules have been proposed for the diagnosis and monitoring of DKD. Various methods have been used to detect intact podocytes and podocyte-derived microvesicles in urine, including centrifugation, visualization, and molecular quantification. Quantification of podocyte-specific protein targets and messenger RNA levels can be performed by Western blotting or enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. At present, many of these techniques are expensive and labor-intensive, all limiting their widespread use in routine clinical tests. While the potential of urinary podocyte markers for monitoring and risk stratification of DKD has been explored, systematic studies and external validation are lacking in the current literature. Standardization and automation of laboratory methods should be a priority for future research, and the added value of these methods to routine clinical tests should be defined.
PubMed: 38325865
DOI: 10.23876/j.krcp.23.109 -
Biomedicines Apr 2024Recent studies of Cardiovascular-Kidney-Metabolic Syndrome (CKMS) indicate that elevated concentrations of derivatives of phospholipids (ceramide, sphingosine), oxidized... (Review)
Review
Recent studies of Cardiovascular-Kidney-Metabolic Syndrome (CKMS) indicate that elevated concentrations of derivatives of phospholipids (ceramide, sphingosine), oxidized LDL, and lipoproteins (a, b) are toxic to kidney and heart function. Energy production for renal proximal tubule resorption of critical fuels and electrolytes is required for homeostasis. Cardiac energy for ventricular contraction/relaxation is preferentially supplied by long chain fatty acids. Metabolism of long chain fatty acids is accomplished within the cardiomyocyte cytoplasm and mitochondria by means of the glycolytic, tricarboxylic acid, and electron transport cycles. Toxic lipids and excessive lipid concentrations may inhibit cardiac function. Cardiac contraction requires calcium movement from the sarcoplasmic reticulum from a high to a low concentration at relatively low energy cost. Cardiac relaxation involves calcium return to the sarcoplasmic reticulum from a lower to a higher concentration and requires more energy consumption. Diastolic cardiac dysfunction occurs when cardiomyocyte energy conversion is inadequate. Diastolic dysfunction from diminished ATP availability occurs in the presence of inadequate blood pressure, glycemia, or lipid control and may lead to heart failure. Similar disruption of renal proximal tubular resorption of fuels/electrolytes has been found to be associated with phospholipid (sphingolipid) accumulation. Elevated concentrations of tissue oxidized low-density lipoprotein cholesterols are associated with loss of filtration efficiency at the level of the renal glomerular podocyte. Macroscopically excessive deposits of epicardial and intra-nephric adipose are associated with vascular pathology, fibrosis, and inhibition of essential functions in both heart and kidney. Chronic triglyceride accumulation is associated with fibrosis of the liver, cardiac and renal structures. Successful liver, kidney, or cardiac allograft of these vital organs does not eliminate the risk of lipid toxicity. Lipid lowering therapy may assist in protecting vital organ function before and after allograft transplantation.
PubMed: 38790940
DOI: 10.3390/biomedicines12050978