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Cell Communication and Signaling : CCS Oct 2023Diabetic kidney disease (DKD) is a major cause of end-stage renal disease and imposes a heavy global economic burden; however, little is known about its complicated... (Review)
Review
Diabetic kidney disease (DKD) is a major cause of end-stage renal disease and imposes a heavy global economic burden; however, little is known about its complicated pathophysiology. Investigating the cellular crosstalk involved in DKD is a promising avenue for gaining a better understanding of its pathogenesis. Nonetheless, the cellular crosstalk of podocytes and endothelial cells in DKD is better understood than that of mesangial cells (MCs) and renal tubular epithelial cells (TECs). As the significance of MCs and TECs in DKD pathophysiology has recently become more apparent, we reviewed the existing literature on the cellular crosstalk of MCs and TECs in the context of DKD to acquire a comprehensive understanding of their cellular communication. Insights into the complicated mechanisms underlying the pathophysiology of DKD would improve its early detection, care, and prognosis. Video Abstract.
Topics: Humans; Diabetic Nephropathies; Mesangial Cells; Endothelial Cells; Epithelial Cells; Podocytes; Diabetes Mellitus
PubMed: 37845726
DOI: 10.1186/s12964-023-01323-w -
Clinica Chimica Acta; International... Jun 2024Diabetic nephropathy (DN), a significant consequence of diabetes, is associated with adverse cardiovascular and renal disease as well as mortality. Although... (Review)
Review
Diabetic nephropathy (DN), a significant consequence of diabetes, is associated with adverse cardiovascular and renal disease as well as mortality. Although microalbuminuria is considered the best non-invasive marker for DN, better predictive markers are needed of sufficient sensitivity and specificity to detect disease in general and in early disease specifically. Even prior to appearance of microalbuminuria, urinary biomarkers increase in diabetics and can serve as accurate nephropathy biomarkers even in normoalbuminuria. In this review, a number of novel urine biomarkers including those reflecting kidney damage caused by glomerular/podocyte damage, tubular damage, oxidative stress, inflammation, and intrarenal renin-angiotensin system activation are discussed. Our review also includes emerging biomarkers such as urinary microRNAs. These short noncoding miRNAs regulate gene expression and could be utilized to identify potential novel biomarkers in DN development and progression. .
PubMed: 38844018
DOI: 10.1016/j.cca.2024.119762 -
Free Radical Biology & Medicine Nov 2023Podocyte injury is a hallmark of glomerular disease and one of the leading causes of chronic kidney disease (CKD). Peroxisome proliferator-activated receptor α (PPARα)...
Podocyte injury is a hallmark of glomerular disease and one of the leading causes of chronic kidney disease (CKD). Peroxisome proliferator-activated receptor α (PPARα) plays a key role in podocyte fatty acid oxidation (FAO). However, the underlying regulatory mechanisms remain unresolved. Trim63 is an E3 ubiquitin ligase that has been shown to inhibit PPARα activity; however, its role in fatty acid metabolism in the kidney has not been elucidated to date. In this study, we investigated the effects of overexpression and knockdown of Trim63 in Adriamycin (ADR)-induced nephropathy and diabetic nephropathy models and a podocyte cell line. In both rodents and human patients with proteinuric CKD, Trim63 was upregulated, particularly in the podocytes of injured glomeruli. In the ADR-induced nephropathy model, ectopic Trim63 application aggravated FAO deficiency and mitochondrial dysfunction and triggered intense lipid deposition, podocyte injury, and proteinuria. Notably, Trim63 inhibition alleviated FAO deficiency and mitochondrial dysfunction, and markedly restored podocyte injury and renal fibrosis in ADR-induced and diabetic nephropathy (DN) models. Additionally, Trim63 was observed to mediate PPARα ubiquitination and degradation, leading to podocyte injury. We demonstrate the pathological role of Trim63, which was previously unrecognized in kidney tissue, in FAO deficiency and podocyte injury. Targeting Trim63 may represent a viable therapeutic strategy for podocyte injury and proteinuria.
Topics: Humans; Podocytes; PPAR alpha; Diabetic Nephropathies; Ubiquitin-Protein Ligases; Proteinuria; Doxorubicin; Renal Insufficiency, Chronic; Fatty Acids
PubMed: 37793501
DOI: 10.1016/j.freeradbiomed.2023.09.039 -
Cell Proliferation Nov 2023Alteration of metabolic phenotype in podocytes directly contributes to the development of albuminuria and renal injury in conditions of diabetic kidney disease (DKD)....
Alteration of metabolic phenotype in podocytes directly contributes to the development of albuminuria and renal injury in conditions of diabetic kidney disease (DKD). This study aimed to identify and evaluate liver receptor homologue-1 (LRH-1) as a possible therapeutic target that alleviates glutamine (Gln) metabolism disorders and mitigates podocyte injury in DKD. Metabolomic and transcriptomic analyses were performed to characterize amino acid metabolism changes in the glomeruli of diabetic mice. Next, Western blotting, immunohistochemistry assays, and immunofluorescence staining were used to detect the expression of different genes in vitro and in vivo. Furthermore, Gln and glutamate (Glu) content as well as ATP generation were examined. A decrease in LRH-1 and glutaminase 2 (GLS2) expression was detected in diabetic podocytes. Conversely, the administration of LRH-1 agonist (DLPC) upregulated the expression of GLS2 and promoted glutaminolysis, with an improvement in mitochondrial dysfunction and less apoptosis in podocytes compared to those in vehicle-treated db/db mice. Our study indicates the essential role of LRH-1 in governing the Gln metabolism of podocytes, targeting LRH-1 could restore podocytes from diabetes-induced disturbed glutaminolysis in mitochondria.
Topics: Animals; Mice; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Kidney; Kidney Glomerulus; Podocytes
PubMed: 37057309
DOI: 10.1111/cpr.13479 -
Biomedicines Feb 2024The nephrotic syndrome holds significant clinical importance and is characterized by a substantial protein loss in the urine. Damage to the glomerular basement membrane... (Review)
Review
The nephrotic syndrome holds significant clinical importance and is characterized by a substantial protein loss in the urine. Damage to the glomerular basement membrane or podocytes frequently underlies renal protein loss. There is an increasing belief in the involvement of the complement system, a part of the innate immune system, in these conditions. Understanding the interactions between the complement system and glomerular structures continually evolves, challenging the traditional view of the blood-urine barrier as a passive filter. Clinical studies suggest that a precise inhibition of the complement system at various points may soon become feasible. However, a thorough understanding of current knowledge is imperative for planning future therapies in nephrotic glomerular diseases such as membranous glomerulopathy, membranoproliferative glomerulonephritis, lupus nephritis, focal segmental glomerulosclerosis, and minimal change disease. This review provides an overview of the complement system, its interactions with glomerular structures, and insights into specific glomerular diseases exhibiting a nephrotic course. Additionally, we explore new diagnostic tools and future therapeutic approaches.
PubMed: 38398059
DOI: 10.3390/biomedicines12020455 -
The Journal of Pathology Nov 2023As an essential factor in the prognosis of systemic lupus erythematosus (SLE), lupus nephritis (LN) can accelerate the rate at which patients with SLE can transition to...
As an essential factor in the prognosis of systemic lupus erythematosus (SLE), lupus nephritis (LN) can accelerate the rate at which patients with SLE can transition to chronic kidney disease or even end-stage renal disease. Podocytes now appear to be a possible direct target in LN in addition to being prone to collateral damage from glomerular capillary lesions induces by immune complexes and inflammatory processes. The NLRP3 inflammasome is regulated by CCAAT/enhancer-binding protein β (C/EBPβ), which is involved in the pathogenesis of SLE. However, the role and mechanism of C/EBPβ in LN remain unclear. In this investigation, glomerular podocytes treated with LN serum and MRL/lpr mice were employed as in vivo and in vitro models of LN, respectively. In vivo, the expression of C/EBPβ isoforms was detected in kidney specimens of humans and mice with LN. Then we assessed the effect of C/EBPβ inhibition on renal structure and function by injecting RNAi adeno-associated virus of C/EBPβ shRNA into MRL/lpr mice. In vitro, glomerular podocytes were treated with LN serum and C/EBPβ siRNA to explore the role of C/EBPβ in the activation of the AIM2 inflammasome and podocyte injury. C/EBPβ-LAP and C/EBPβ-LIP were significantly overexpressed in kidney tissue samples from LN patients and mice, and C/EBPβ inhibition significantly alleviated renal function damage and ameliorated renal structural deficiencies. Inflammatory pathways downstream from the AIM2 inflammasome could be suppressed by C/EBPβ knockdown. Furthermore, the upregulation of C/EBPβ-LAP could activate the AIM2 inflammasome and podocyte pyroptosis by binding to the promoters of AIM2 and CASPASE1 to enhance their expression, and the knockdown of AIM2 or (and) caspase-1 reversed the effects of C/EBPβ-LAP overexpression. Interestingly, C/EBPβ-LIP overexpression could transcriptionally inhibit IRAG and promote Ca release-mediated activation of the AIM2 inflammasome. This finding suggests that C/EBPβ is not only involved in the regulation of the expression of key proteins of the AIM2 inflammasome but also affects the polymerization of key proteins of the AIM2 inflammasome through the regulation of Ca release. In conclusion, this study provides a new idea for studying the regulatory mechanism of C/EBPβ and provides a theoretical basis for the early diagnosis and treatment of LN in the future. © 2023 The Pathological Society of Great Britain and Ireland.
PubMed: 37602503
DOI: 10.1002/path.6174 -
Pediatric Nephrology (Berlin, Germany) Dec 2023Biological and biomedical research using Drosophila melanogaster as a model organism has gained recognition through several Nobel prizes within the last 100 years.... (Review)
Review
Biological and biomedical research using Drosophila melanogaster as a model organism has gained recognition through several Nobel prizes within the last 100 years. Drosophila exhibits several advantages when compared to other in vivo models such as mice and rats, as its life cycle is very short, animal maintenance is easy and inexpensive and a huge variety of transgenic strains and tools are publicly available. Moreover, more than 70% of human disease-causing genes are highly conserved in the fruit fly. Here, we explain the use of Drosophila in nephrology research and describe two kidney tissues, Malpighian tubules and the nephrocytes. The latter are the homologous cells to mammalian glomerular podocytes and helped to provide insights into a variety of signaling pathways due to the high morphological similarities and the conserved molecular make-up between nephrocytes and podocytes. In recent years, nephrocytes have also been used to study inter-organ communication as links between nephrocytes and the heart, the immune system and the muscles have been described. In addition, other tissues such as the eye and the reproductive system can be used to study the functional role of proteins being part of the kidney filtration barrier.
Topics: Humans; Animals; Rats; Mice; Drosophila; Drosophila melanogaster; Drosophila Proteins; Kidney; Animals, Genetically Modified; Podocytes; Mammals
PubMed: 37171583
DOI: 10.1007/s00467-023-05996-w -
In Vitro Cellular & Developmental... Oct 2023Ferroptosis is a newly discovered form of cell death characterized by intracellular iron accumulation and subsequent lipid peroxidation, which has been identified in...
Ferroptosis is a newly discovered form of cell death characterized by intracellular iron accumulation and subsequent lipid peroxidation, which has been identified in various pathological processes, such as acute kidney injury (AKI). Ulinastatin (UTI), known as an antioxidant and anti-inflammatory, has been reported to prevent kidney injury. Here, we investigated the protective effects of UTI on LPS-induced podocyte ferroptosis in vivo and in vitro. Conditionally immortalized mouse podocyte was exposed to LPS in the presence or absence of UTI in vitro for 48 h. The levels of reactive oxygen species (ROS) and intracellular Fe were detected to value the effect of UTI treatment on the podocyte cell ferroptosis. We also evaluated the influence of UTI on kidney injury in vivo. LPS-induced mice were treated with vehicle or UTI at 50 U/g/d for 6 wk. We identified the important function of UTI in repressing ferroptosis and ameliorating podocyte injury. The treatment of UTI reduced accumulation of Fe and lipid ROS in podocyte. The cell proliferation was induced by UTI compared with the LPS-treated group in vitro. UTI attenuated the podocyte cytoskeletal as well. Regarding the mechanism, we found that UTI upregulated solute carrier family 7 member 11 (SLC7A11) expression by reducing miR-144-3p in the cells. The overexpression of miR-144-3p blocked the protective role of UTI in podocyte ferroptosis. MiR-144-3p/SLC7A11 axis was involved in UTI-mediated podocyte cell proliferation in vitro. Furthermore, the treatment of UTI repressed podocyte injury and proteinuria in vivo, and the level of miR-144-3p was decreased while SLC7A11 expression was increased in comparison with the model mice. UTI prevents LPS-induced podocyte ferroptosis and subsequent renal dysfunction through miR-144-3p/SLC7A11 axis. These findings might provide a potential novel therapeutic option for AKI and other renal diseases affecting podocyte.
Topics: Animals; Mice; Acute Kidney Injury; Ferroptosis; Lipopolysaccharides; MicroRNAs; Podocytes; Reactive Oxygen Species
PubMed: 37819479
DOI: 10.1007/s11626-023-00814-x -
Molecular Medicine (Cambridge, Mass.) Oct 2023Diabetic kidney disease (DKD) is the main cause of end-stage renal disease, and its clinical manifestations are progressive proteinuria, decreased glomerular filtration... (Review)
Review
Diabetic kidney disease (DKD) is the main cause of end-stage renal disease, and its clinical manifestations are progressive proteinuria, decreased glomerular filtration rate, and renal failure. The injury and death of glomerular podocytes are the keys to DKD. Currently, a variety of cell death modes have been identified in podocytes, including apoptosis, autophagy, endoplasmic reticulum (ER) stress, pyroptosis, necroptosis, ferroptosis, mitotic catastrophe, etc. The signaling pathways leading to these cell death processes are interconnected and can be activated simultaneously or in parallel. They are essential for cell survival and death that determine the fate of cells. With the deepening of the research on the mechanism of cell death, more and more researchers have devoted their attention to the underlying pathologic research and the drug therapy research of DKD. In this paper, we discussed the podocyte physiologic role and DKD processes. We also provide an overview of the types and specific mechanisms involved in each type of cell death in DKD, as well as related targeted therapy methods and drugs are reviewed. In the last part we discuss the complexity and potential crosstalk between various modes of cell death, which will help improve the understanding of podocyte death and lay a foundation for new and ideal targeted therapy strategies for DKD treatment in the future.
Topics: Humans; Diabetic Nephropathies; Podocytes; Cell Death; Apoptosis; Epithelial Cells; Diabetes Mellitus
PubMed: 37828444
DOI: 10.1186/s10020-023-00732-4 -
Free Radical Biology & Medicine Oct 2023Membranous nephropathy (MN) patients are diagnosed by the presence of phospholipase A receptor (PLA2R) before they progress to renal failure. However, the...
Membranous nephropathy (MN) patients are diagnosed by the presence of phospholipase A receptor (PLA2R) before they progress to renal failure. However, the subepithelium-like immunocomplex deposit-mediated downstream molecular pathways are poorly understood. The aryl hydrocarbon receptor (AHR), NF-ƙB and Nrf2 pathways play central roles in the pathogenesis and progression of chronic kidney disease. However, their mutual effects on MN require further examination. Thus, we investigated the effect of AHR signalling on the NF-ƙB and Nrf2 pathways in IMN patients, cationic bovine serum albumin (CBSA)-injected rats and zymosan activation serum (ZAS)-treated podocytes. IMN patients show significantly decreased serum total protein and albumin levels, increased urine protein levels and intrarenal IgG and PLA2R protein expression in glomeruli compared with controls. IMN patients exhibited increased mRNA expression of intrarenal AHR and its target genes, including CYP1A1, CYP1A2, CYP1B1 and COX-2. This increase was accompanied by significantly upregulated protein expression of CD3, NF-ƙB p65 and COX-2 and significantly downregulated Nrf2 and HO-1 expression. Similarly, CBSA-induced rats showed severe proteinuria and activated intrarenal AHR signalling. This was accompanied by significantly upregulated protein expression of intrarenal p-IκBα, NF-κB p65 and its gene products, including COX-2, MCP-1, iNOS, 12-LOX, p47 and p67, and significantly downregulated protein expression of Nrf2 and its gene products, including HO-1, catalase, GCLC, GCLM, MnSOD and NQO1. These results were further verified in ZAS-induced podocytes. Treatment with the AHR antagonist CH223191 and AHRsiRNA significantly preserved podocyte-specific protein expression and improved the NF-ƙB and Nrf2 pathways in ZAS-induced podocytes. In contrast, similar results were obtained in ZAS-induced podocytes treated with the NF-ƙB inhibitor BAY 11-7082 and NF-κBp65 siRNA. However, neither method had a significant effect on AHR signalling. Collectively, these results indicate that the NF-ƙB pathway is a downstream target of AHR signalling. Our findings suggest that blocking AHR signalling inhibits oxidative stress and inflammation, thereby improving proteinuria and renal injury.
Topics: Animals; Rats; Cyclooxygenase 2; Glomerulonephritis, Membranous; Inflammation; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Proteinuria; Receptors, Aryl Hydrocarbon; Humans; Podocytes
PubMed: 37451370
DOI: 10.1016/j.freeradbiomed.2023.07.014