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Molecular Medicine Reports Nov 2023Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder caused by the loss of tolerance to endogenous nuclear antigens such as double‑stranded DNA,... (Review)
Review
Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder caused by the loss of tolerance to endogenous nuclear antigens such as double‑stranded DNA, leading to the proliferation of T cells and subsequent activation of B cells, which results in serious organ damage and life‑threatening complications such as lupus nephritis. Lupus nephritis (LN) develops as a frequent complication of SLE, accounting for >60% of SLE cases, and is characterized by proteinuria and heterogeneous histopathological findings. Glomerular injury serves a role in proteinuria as podocyte damage is the leading contributor. Numerous studies have reported that podocytes are involved in the immune response that promotes LN progression. In LN, immune complex deposition stimulates dendritic cells to secrete inflammatory cytokines that activate T cells and B cells. B cells secrete autoantibodies that attack and damage the renal podocytes, leading to renal podocyte injury. The injured podocytes trigger inflammatory cells through the expression of toll‑like receptors and trigger T cells through major histocompatibility complexes and CD86, thereby participating in the local immune response and the exacerbation of podocyte injury. Based on the existing literature, the present review summarizes the research progress of podocytes in LN under the local immune microenvironment of the kidney, explores the mechanism of podocyte injury under the immune microenvironment, and evaluates podocytes as a potential therapeutic target for LN.
Topics: Humans; Lupus Nephritis; Podocytes; Kidney; Lupus Erythematosus, Systemic; Proteinuria
PubMed: 37711069
DOI: 10.3892/mmr.2023.13091 -
Radiotherapy and Oncology : Journal of... Oct 2023Radiation nephropathy (RN) can be a severe late complication for patients treated with radiotherapy (RT) targeting abdominal and paraspinal tumors. Recent studies...
BACKGROUND
Radiation nephropathy (RN) can be a severe late complication for patients treated with radiotherapy (RT) targeting abdominal and paraspinal tumors. Recent studies investigating the mechanisms of RT-mediated injury in the kidney have demonstrated that RT disrupts the cellular integrity of renal podocytes leading to cell death and loss of renal function.
AIM
To determine if RT-induced renal dysfunction is associated with alterations in podocyte and glomerular function, and whether RT-induced podocyte alterations were associated with changes in the glomerular basement membrane (GBM).
METHODS
C57BL/6 mice were treated with focal bilateral X-irradiation using a single dose (SD) of 4 Gy, 10 Gy, or 14 Gy or fractionated dosing (FD) of 5x6Gy or 24x2Gy. Then, 10-40 weeks after RT parameters of renal function were measured, along with glomerular filtration rate (GFR) and glomerular histology, as well as ultrastructural changes in GBM by transmission electron microscopy.
RESULTS
RT treatment resulted in persistent changes in renal function beginning at 10 weeks with little recovery up to 40 weeks post RT. Dose dependent changes were seen with increasing SD but no functional sparing was evident after FD. RT-induced loss of renal function was associated with expansion of the GBM and significant increases in foot process width, and associated with significant reduction in GFR, podocyte loss, and renal fibrosis.
CONCLUSION
For the first time, these data show that expansion of the GBM is one consequence of radiation injury, and disarrangement of the GBM might be associated with the death of podocytes. These data shed new light on the role podocyte injury and GBM in RT-induced renal dysfunction.
Topics: Mice; Animals; Disease Models, Animal; Mice, Inbred C57BL; Kidney Glomerulus; Kidney Diseases; Podocytes; Radiation Injuries
PubMed: 37468066
DOI: 10.1016/j.radonc.2023.109813 -
American Journal of Physiology. Renal... Nov 2019Diabetic kidney disease (DKD) affects ∼40% of patients with diabetes and is associated with high mortality rates. Among different cellular targets in DKD, podocytes,... (Review)
Review
Diabetic kidney disease (DKD) affects ∼40% of patients with diabetes and is associated with high mortality rates. Among different cellular targets in DKD, podocytes, highly specialized epithelial cells of the glomerular filtration barrier, are injured in the early stages of DKD. Both clinical and experimental data support the role of preserved insulin signaling as a major contributor to podocyte function and survival. However, little is known about the key modulators of podocyte insulin signaling. This review summarizes the novel knowledge that intracellular lipids such as cholesterol and sphingolipids are major determinants of podocyte insulin signaling. In particular, the implications of these lipids on DKD development, progression, and treatment will be addressed.
Topics: Diabetic Nephropathies; Humans; Insulin; Lipid Metabolism; Podocytes; Signal Transduction
PubMed: 31545927
DOI: 10.1152/ajprenal.00379.2019 -
Journal of Nephrology Jan 2023Podocytes are terminally differentiated epithelial cells of the renal glomerular tuft and these highly specialized cells are essential for the integrity of the slit... (Review)
Review
Podocytes are terminally differentiated epithelial cells of the renal glomerular tuft and these highly specialized cells are essential for the integrity of the slit diaphragm. The biological function of podocytes is primarily based on a complex ramified structure that requires sufficient nutrients and a large supply of energy in support of their unique structure and function in the glomeruli. Of note, the dysregulation of nutrient signaling and energy metabolic pathways in podocytes has been associated with a range of kidney diseases i.e., diabetic nephropathy. Therefore, nutrient-related and energy metabolic signaling pathways are critical to maintaining podocyte homeostasis and the pathogenesis of podocyte injury. Recently, a growing body of evidence has indicated that nutrient starvation induces autophagy, which suggests crosstalk between nutritional signaling with the modulation of autophagy for podocytes to adapt to nutrient deprivation. In this review, the current knowledge and advancement in the understanding of nutrient sensing, signaling, and autophagy in the podocyte biology, injury, and pathogenesis of kidney diseases is summarized. Based on the existing findings, the implications and perspective to target these signaling pathways and autophagy in podocytes during the development of novel preventive and therapeutic strategies in patients with podocyte injury-associated kidney diseases are discussed.
Topics: Humans; Podocytes; Kidney Glomerulus; Diabetic Nephropathies; Autophagy; Nutrients
PubMed: 35704261
DOI: 10.1007/s40620-022-01365-2 -
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 -
Advances in Clinical and Experimental... Dec 2019Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD), both in the USA and in Europe; moreover, its incidence is rising worldwide. The... (Review)
Review
Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD), both in the USA and in Europe; moreover, its incidence is rising worldwide. The main laboratory markers of DN progression are albuminuria and a reduction in glomerular filtration rates, although progression of the disease has been observed even in the absence of these biomarkers. Renal impairment, associated with diabetes, results from damage to the glomerular filtration barrier, at the level of highly differentiated glomerular epithelial cells: podocytes. These cells regulate glomerular filtration and many immunological processes occurring at this level. The earliest possible diagnosis of diabetic kidney disease (DKD) and implementation of intensive treatment offers the possibility of preventing or substantially delaying the onset of ESRD. In this article, we review various urinary biomarkers linked with glomerular podocyte cytophysiology as potentially sensitive diagnostic tools for the early detection of DKD. These biomarkers have predictive potential for assessing the progression toward end-stage nephropathy.
Topics: Albuminuria; Diabetic Nephropathies; Glomerular Filtration Rate; Humans; Kidney Glomerulus; Podocytes
PubMed: 31851794
DOI: 10.17219/acem/104534 -
Renal Failure 2023: Idiopathic membranous nephropathy is widely recognized as an autoimmune kidney disease that is accompanied by the discovery of several autoantibodies, and the antibody...
: Idiopathic membranous nephropathy is widely recognized as an autoimmune kidney disease that is accompanied by the discovery of several autoantibodies, and the antibody subclass in the circulation of patients with iMN is mainly IgG. However, the direct pathogenic effect of the containing anti-PLA2R IgG antibody on podocytes is not clear. A protein G affinity chromatography column was used to purify serum IgG antibodies. Containing anti-PLA2R IgG antibodies from iMN patients and IgG from healthy controls were also obtained. Based on the established podocyte culture system, purified IgG antibodies from the two groups were used to stimulate podocytes, and the expression of essential podocyte proteins (podocin), the levels of inflammatory cytokines in the cell supernatant, cytoskeletal disorders, and podocyte apoptosis were analyzed. Compared with that in the normal IgG group, the expression of podocin and podocin mRNA was reduced ( = 0.016 and = 0.005, respectively), the fluorescence intensity of podocin on the surface of podocytes was reduced, the cytoskeleton of podocytes was disordered and reorganized, and the ratio of podocyte apoptosis was increased in the iMN group ( = 0.008). The containing anti-PLA2R IgG antibody might have a direct damaging effect on podocytes in idiopathic membranous nephropathy.
Topics: Humans; Glomerulonephritis, Membranous; Podocytes; Autoantibodies; Kidney; Immunoglobulin G
PubMed: 37905942
DOI: 10.1080/0886022X.2023.2271986 -
Cells Apr 2021Vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2 are the main targets of antiangiogenic therapies, and proteinuria is one of the common adverse... (Review)
Review
Vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2 are the main targets of antiangiogenic therapies, and proteinuria is one of the common adverse events associated with the inhibition of the VEGFA/VEGFR2 pathway. The proteinuric kidney damage induced by VEGFR2 tyrosine kinase inhibitors (TKIs) is characterized by podocyte foot process effacement. TKI therapy promotes the formation of abnormal endothelial‒podocyte crosstalk, which plays a key role in TKI-induced podocyte injury and proteinuric nephropathy. This review article summarizes the underlying mechanism by which the abnormal endothelial‒podocyte crosstalk mediates podocyte injury and discusses the possible molecules and signal pathways involved in abnormal endothelial‒podocyte crosstalk. What is more, we highlight the molecules involved in podocyte injury and determine the essential roles of Rac1 and Cdc42; this provides evidence for exploring the abnormal endothelial‒podocyte crosstalk in TKI-induced nephrotoxicity.
Topics: Actin Cytoskeleton; Animals; Cell Movement; Endothelial Cells; Humans; Kidney; Podocytes; Protein Kinase Inhibitors
PubMed: 33921219
DOI: 10.3390/cells10040869 -
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 -
Kidney International Nov 2020Obesity and hyperlipidemia are the most prevalent independent risk factors of ESRD, suggesting that lipid accumulation is detrimental to renal function. The origin of...
Obesity and hyperlipidemia are the most prevalent independent risk factors of ESRD, suggesting that lipid accumulation is detrimental to renal function. The origin of lipid accumulation (a common feature in podocyte injury) and its pathophysiological relevance are unknown. This commentary discusses the finding by Liu et al. that deficiency of the endoplasmic reticulum enzyme SOAT1, which metabolizes cholesterol to cholesterol esters, attenuates renal/podocyte injury in murine models of diabetes and Alport's syndrome.
Topics: Animals; Diabetes Mellitus; Kidney; Lipid Metabolism; Mice; Nephritis, Hereditary; Podocytes
PubMed: 33126971
DOI: 10.1016/j.kint.2020.07.008