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Aging Jul 2023The decrease in the podocyte's lifespan and health-span that typify healthy kidney aging cause a decrease in their normal structure, physiology and function. The ability...
The decrease in the podocyte's lifespan and health-span that typify healthy kidney aging cause a decrease in their normal structure, physiology and function. The ability to halt and even reverse these changes becomes clinically relevant when disease is superimposed on an aged kidney. RNA-sequencing of podocytes from middle-aged mice showed an inflammatory phenotype with increases in the NLRP3 inflammasome, signaling for IL2/Stat5, IL6 and TNF, interferon gamma response, allograft rejection and complement, consistent with inflammaging. Furthermore, injury-induced NLRP3 signaling in podocytes was further augmented in aged mice compared to young ones. The NLRP3 inflammasome (NLRP3, Caspase-1, IL1β IL-18) was also increased in podocytes of middle-aged humans. Higher transcript expression for NLRP3 in human glomeruli was accompanied by reduced podocyte density and increased global glomerulosclerosis and glomerular volume. Pharmacological inhibition of NLRP3 with MCC950, or gene deletion, reduced podocyte senescence and the genes typifying aging in middle-aged mice, which was accompanied by an improved podocyte lifespan and health-span. Moreover, modeling the injury-dependent increase in NLRP3 signaling in human kidney organoids confirmed the anti-senescence effect of MC9950. Finally, NLRP3 also impacted liver aging. Together, these results suggest a critical role for the NLRP3 inflammasome in podocyte and liver aging.
Topics: Humans; Animals; Mice; Middle Aged; Podocytes; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Kidney Glomerulus; Aging
PubMed: 37487005
DOI: 10.18632/aging.204897 -
Kidney International Nov 2023The phospholipase A2 receptor 1 (PLA2R1) is the major target antigen in patients with membranous nephropathy (MN), an antibody-mediated autoimmune glomerular disease....
The phospholipase A2 receptor 1 (PLA2R1) is the major target antigen in patients with membranous nephropathy (MN), an antibody-mediated autoimmune glomerular disease. Investigation of MN pathogenesis has been hampered by the lack of reliable animal models. Here, we overcome this issue by generating a transgenic mouse line expressing a chimeric PLA2R1 (chPLA2R1) consisting of three human PLA2R1 domains (cysteine-rich, fibronectin type-II and CTLD1) and seven murine PLA2R1 domains (CTLD2-8) specifically in podocytes. Mice expressing the chPLA2R1 were healthy at birth and showed no major glomerular alterations when compared to mice with a wild-type PLA2R1 status. Upon active immunization with human PLA2R1 (hPLA2R1), chPLA2R1-positive mice developed anti-hPLA2R1 antibodies, a nephrotic syndrome, and all major histological features of MN, including granular deposition of mouse IgG and complement components in immunofluorescence and subepithelial electron-dense deposits and podocyte foot process effacement in electron microscopy. In order to investigate the role of the complement system in this model, we further crossed chPLA2R1-positive mice with mice lacking the central complement component C3 (C3 mice). Upon immunization with hPLA2R1, chPLA2R1-positive C3 mice had substantially less severe albuminuria and nephrotic syndrome when compared to chPLA2R1-positive mice with a wild-type C3 status. In conclusion, we introduce a novel active immunization model of PLA2R1-associated MN and demonstrate a pathogenic role of the complement system in this model.
Topics: Humans; Mice; Animals; Glomerulonephritis, Membranous; Nephrotic Syndrome; Receptors, Phospholipase A2; Autoantibodies; Autoimmune Diseases; Mice, Transgenic; Vaccination; Complement C3; Disease Models, Animal
PubMed: 37598854
DOI: 10.1016/j.kint.2023.07.024 -
Renal Failure Dec 2023Hepatitis B virus-associated glomerulonephritis (HBV-GN) is one of the main types of secondary glomerular diseases, and podocyte injury is an important pathogenic...
INTRODUCTION
Hepatitis B virus-associated glomerulonephritis (HBV-GN) is one of the main types of secondary glomerular diseases, and podocyte injury is an important pathogenic mechanism of HBV-GN, participating in the occurrence and development of HBV-GN. However, the specific mechanism of podocyte injury remains to be studied.
METHODS
Human renal podocytes cultured were divided into six groups. The podocyte morphology was observed under a transmission electron microscope, and the expression of M-type phospholipase A receptor (M-PLAR) on the podocyte membrane was observed by indirect immunofluorescence staining under a fluorescence microscope. The pyroptosis rate and reactive oxygen species (ROS) of podocytes were assessed by FLICA/PI double staining and flow cytometry. Western blot (WB) and quantitative real-time PCR (qPCR) were used to determine the expression of PLAR, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing card (ASC), caspase-1, IL-1β, and IL-18.
RESULTS
Hepatitis B virus X (HBx) transfected into human renal podocytes induced the overexpression of PLAR. Moreover, the overexpressed PLAR combined with secretory phospholipase A group IB (sPLA-IB) aggravated podocyte injury and increased the pyroptosis rate. In addition, the expression of ROS, the NLRP3 inflammasome and downstream inflammatory factors was increased. In contrast, after inhibiting the expression of PLAR and ROS, podocyte damage was alleviated, and the pyroptosis rate and the expression of genes related to the ROS-NLRP3 signaling pathway were decreased.
CONCLUSION
HBx-induced PLAR overexpression on the podocyte membrane can significantly upregulate the ROS-NLRP3 signaling pathway, thereby mediating podocyte pyroptosis.
Topics: Humans; Podocytes; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Reactive Oxygen Species; Signal Transduction; Phospholipases; Polyesters
PubMed: 36698326
DOI: 10.1080/0886022X.2023.2170808 -
FASEB Journal : Official Publication of... Nov 2023Mitochondrial dysfunction plays an important role in the onset and progression of podocyte injury and proteinuria. However, the process by which the change in the...
Mitochondrial dysfunction plays an important role in the onset and progression of podocyte injury and proteinuria. However, the process by which the change in the podocyte mitochondria occurs is not well understood. Uncoupling protein 2 (UCP2) is a mitochondrial anion carrier protein, which is located in the mitochondrial inner membrane. Here, we reported that mice with podocyte-specific Ucp2 deficiency developed podocytopathy with proteinuria with aging. Furthermore, those mice exhibited increased proteinuria in experimental models evoked by Adriamycin. Our findings suggest that UCP2 mediates mitochondrial dysfunction by regulating mitochondrial dynamic balance. Ucp2-deleted podocytes exhibited increased mitochondrial fission and deficient in ATP production. Mechanistically, opacity protein 1 (OPA1), a key protein in fusion of mitochondrial inner membrane, was regulated by UCP2. Ucp2 deficiency promoted proteolysis of OPA1 by activation OMA1 which belongs to mitochondrial inner membrane zinc metalloprotease. Those finding demonstrate the role of UCP2 in mitochondrial dynamics in podocytes and provide new insights into pathogenesis associated with podocyte injury and proteinuria.
Topics: Animals; Mice; GTP Phosphohydrolases; Metalloproteases; Mitochondrial Dynamics; Mitochondrial Proteins; Podocytes; Proteinuria; Proteolysis; Uncoupling Protein 2
PubMed: 37874273
DOI: 10.1096/fj.202301055R -
Frontiers in Pharmacology 2024The most prevalent and devastating form of organ damage in systemic lupus erythematosus (SLE) is lupus nephritis (LN). LN is characterized by glomerular injury,... (Review)
Review
The most prevalent and devastating form of organ damage in systemic lupus erythematosus (SLE) is lupus nephritis (LN). LN is characterized by glomerular injury, inflammation, cell proliferation, and necrosis, leading to podocyte injury and tubular epithelial cell damage. Assays for urine biomarkers have demonstrated significant promise in the early detection of LN, evaluation of disease activity, and tracking of reaction to therapy. This is because they are non-invasive, allow for frequent monitoring and easy self-collection, transport and storage. Podocyte injury is believed to be a essential factor in LN. The extent and type of podocyte injury could be connected to the severity of proteinuria, making podocyte-derived cellular debris and injury-related urinary proteins potential markers for the diagnosis and monitoring of LN. This article focuses on studies examining urinary biomarkers associated with podocyte injury in LN, offering fresh perspectives on the application of biomarkers in the early detection and management of LN.
PubMed: 38313309
DOI: 10.3389/fphar.2024.1324540 -
Biomedicine & Pharmacotherapy =... Nov 2023Podocyte injury is the common initiating event in focal segmental glomerulosclerosis (FSGS). Oxidative stress and inflammation mediate podocyte injury in FSGS. NRF2...
Podocyte injury is the common initiating event in focal segmental glomerulosclerosis (FSGS). Oxidative stress and inflammation mediate podocyte injury in FSGS. NRF2 pathway regulates the constitutive and inducible transcription of various genes that encode antioxidant proteins and anti-inflammatory proteins and have pivotal roles in the defense against cellular oxidative stress. In this study, we used adriamycin-induced nephropathy (ADR) in mice as a model of FSGS to confirm that CDDO-Me treatment ameliorated adriamycin-induced kidney damage by improving renal function and kidney histology. CDDO-Me inhibited the level of oxidative stress, inflammation, and apoptosis in adriamycin-induced podocyte injury by activating NRF2 pathway in vivo and in vitro. Furthermore, CDDO-Me stabled the cytoskeleton by regulating NRF2/srGAP2a pathway. Together, these findings show that by activating NRF2 pathway, CDDO-Me could be a therapeutic strategy to prevent the adverse effects of adriamycin-induced podocyte injury.
Topics: Mice; Animals; Glomerulosclerosis, Focal Segmental; Doxorubicin; Podocytes; NF-E2-Related Factor 2; Kidney Diseases; Actin Cytoskeleton; Oxidative Stress; Inflammation
PubMed: 37801905
DOI: 10.1016/j.biopha.2023.115617 -
Liver International : Official Journal... Jun 2024Accumulating epidemiological evidence shows that the patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 G allele, which is the most robust genetic... (Review)
Review
Accumulating epidemiological evidence shows that the patatin-like phospholipase domain-containing protein-3 (PNPLA3) rs738409 G allele, which is the most robust genetic variant associated with greater susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD), is significantly associated with impaired kidney function in both adults and children, regardless of the presence of common renal risk factors, MASLD severity, and other potential confounders. Although some prospective studies have reported a significant association between the PNPLA3 rs738409 G allele and the increased risk of developing chronic kidney disease (CKD), the epidemiological evidence about a possible direct effect of the PNPLA3 rs738409 G allele on the risk of developing CKD is still limited. Experimentally, PNPLA3 is expressed in renal podocytes, pericytes, and proximal tubule cells, thus supporting the notion that the mutant PNPLA3 protein may play a role in developing renal steatosis and fibrosis. However, it cannot be ruled out that a part of the adverse effect of the PNPLA3 rs738409 G allele on kidney function may be driven by a direct impact of this genetic variant on the development and progression of MASLD. It is possible to hypothesize that identifying the PNPLA3 genotype might help identify individuals at higher risk of CKD and those at greater risk of advanced MASLD. In this narrative minireview, we summarize the current epidemiological data about the association between the PNPLA3 rs738409 G allele and the risk of CKD and abnormal albuminuria. We also briefly discuss the putative biological mechanisms underpinning this association and its potential and future clinical implications.
PubMed: 38873992
DOI: 10.1111/liv.16010 -
Nephrology, Dialysis, Transplantation :... Sep 2023This review summarizes the pathomorphological sequences of nephron loss in human diabetic nephropathy (DN). The relevant changes may be derived from two major... (Review)
Review
This review summarizes the pathomorphological sequences of nephron loss in human diabetic nephropathy (DN). The relevant changes may be derived from two major derangements. First, a failure in the turnover of the glomerular basement membrane (GBM) based on an increased production of GBM components by podocytes and endothelial cells leading to the thickening of the GBM and accumulation of worn-out GBM in the mesangium. This failure may account for the direct pathway to glomerular compaction and sclerosis based on the continuous deposition of undegraded GBM material in the mesangium. Second, an increased leakiness together with an increased propensity of glomerular capillaries to proliferate leads to widespread plasma exudations. Detrimental are those that produce giant insudative spaces within Bowman's capsule, spreading around the entire glomerular circumference and along the glomerulo-tubular junction onto the tubule resulting in tubular obstruction and retroactively to glomerulosclerosis. Tubular atrophy and interstitial fibrosis develop secondarily by transfer of the glomerular damage onto the tubule. Interstitial fibrosis is locally initiated and apparently stimulated by degenerating tubular epithelia. This leads to a focal distribution of interstitial fibrosis and tubular atrophy accompanied by a varying interstitial mononuclear cell infiltration. Spreading of fibrotic areas between intact nephrons, much less to the glomerulus, has not been encountered.
Topics: Humans; Diabetic Nephropathies; Endothelial Cells; Glomerular Basement Membrane; Fibrosis; Atrophy; Diabetes Mellitus
PubMed: 36918205
DOI: 10.1093/ndt/gfad052 -
International Journal of Molecular... Dec 2023Diabetes nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide, and podocyte injury is the central contributor to the progression of DN....
Diabetes nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide, and podocyte injury is the central contributor to the progression of DN. Despite the emerging evidence that has established the importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of DN, abnormal protein O-GlcNAcylation is also augmented. Currently, the mechanism associating these two hyperglycemia-induced disorders remains poorly understood. This study intended to elucidate whether ER stress drives hyper-protein O-GlcNAcylation to cause podocyte injury in DN. We used both type 1 and type 2 DN models to confirm the occurrence of ER stress and excessive protein O-GlcNAcylation, and then podocyte purification was also conducted for further investigation. Nephroseq V5 data were mined and in vitro studies were applied to reveal the involvement of ER stress and hyper-O-GlcNAcylation in podocyte injury. Our results indicated that ER stress was induced in both type 1 and type 2 DN, and the human RNA-seq data from Nephroseq V5 showed that O-GlcNAcylation-related genes were significantly upregulated in the DN patients. We further demonstrated that ER stress occurred prior to hyper-O-GlcNAc modification and that pharmacologically inhibited protein O-GlcNAcylation can help decrease the podocyte apoptosis induced by hyperglycemia. Together, these discoveries will aid in uncovering the activation of the ER stress-O-GlcNAcylation axis in podocyte injury under DN, which will help open up new therapeutic approaches for preventing DN progression.
Topics: Humans; Podocytes; Diabetic Nephropathies; Endoplasmic Reticulum Stress; Proteins; Hyperglycemia; Diabetes Mellitus, Type 2
PubMed: 38139429
DOI: 10.3390/ijms242417603 -
Immunity Jan 2024Tissue factor (TF), which is a member of the cytokine receptor family, promotes coagulation and coagulation-dependent inflammation. TF also exerts protective effects...
Tissue factor (TF), which is a member of the cytokine receptor family, promotes coagulation and coagulation-dependent inflammation. TF also exerts protective effects through unknown mechanisms. Here, we showed that TF bound to interferon-α receptor 1 (IFNAR1) and antagonized its signaling, preventing spontaneous sterile inflammation and maintaining immune homeostasis. Structural modeling and direct binding studies revealed binding of the TF C-terminal fibronectin III domain to IFNAR1, which restricted the expression of interferon-stimulated genes (ISGs). Podocyte-specific loss of TF in mice (Pod) resulted in sterile renal inflammation, characterized by JAK/STAT signaling, proinflammatory cytokine expression, disrupted immune homeostasis, and glomerulopathy. Inhibiting IFNAR1 signaling or loss of Ifnar1 expression in podocytes attenuated these effects in Pod mice. As a heteromer, TF and IFNAR1 were both inactive, while dissociation of the TF-IFNAR1 heteromer promoted TF activity and IFNAR1 signaling. These data suggest that the TF-IFNAR1 heteromer is a molecular switch that controls thrombo-inflammation.
Topics: Animals; Mice; Inflammation; Interferon-alpha; Receptor, Interferon alpha-beta; Signal Transduction; Thromboplastin
PubMed: 38141610
DOI: 10.1016/j.immuni.2023.11.017