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Kidney International May 2024The circadian clock influences a wide range of biological process and controls numerous aspects of physiology to adapt to the daily environmental changes caused by...
The circadian clock influences a wide range of biological process and controls numerous aspects of physiology to adapt to the daily environmental changes caused by Earth's rotation. The kidney clock plays an important role in maintaining tubular function, but its effect on podocytes remains unclear. Here, we found that podocytes expressed CLOCK proteins, and that 2666 glomerular gene transcripts (13.4%), including autophagy related genes, had 24-hour circadian rhythms. Deletion of Clock in podocytes resulted in 1666 gene transcripts with the loss of circadian rhythm including autophagy genes. Podocyte-specific Clock knockout mice at age three and eight months showed deficient autophagy, loss of podocytes and increased albuminuria. Chromatin immunoprecipitation (ChIP) sequence analysis indicated autophagy related genes were targets of CLOCK in podocytes. ChIP-PCR further confirmed Clock binding to the promoter regions of Becn1 and Atg12, two autophagy related genes. Furthermore, the association of CLOCK regulated autophagy with chronic sleep fragmentation and diabetic kidney disease was analyzed. Chronic sleep fragmentation resulted in the loss of glomerular Clock rhythm, inhibition of podocyte autophagy, and proteinuria. Rhythmic oscillations of Clock also disappeared in high glucose treated podocytes and in glomeruli from diabetic mice. Finally, circadian differences in podocyte autophagy were also abolished in diabetic mice. Deletion Clock in podocytes aggravated podocyte injury and proteinuria in diabetic mice. Thus, our findings demonstrate that clock-dependent regulation of autophagy may be essential for podocyte survival. Hence. loss of circadian controlled autophagy may play an important role in podocyte injury and proteinuria.
Topics: Mice; Animals; Podocytes; Diabetes Mellitus, Experimental; Sleep Deprivation; Proteinuria; Diabetic Nephropathies; Mice, Knockout; Autophagy
PubMed: 38387504
DOI: 10.1016/j.kint.2024.01.035 -
Kidney International Reports Sep 2023Podocyte apoptosis is a common mechanism driving progression in Alport syndrome (AS). This study aimed to investigate the mechanism of podocyte apoptosis caused by...
INTRODUCTION
Podocyte apoptosis is a common mechanism driving progression in Alport syndrome (AS). This study aimed to investigate the mechanism of podocyte apoptosis caused by mutations.
METHODS
We recruited patients with autosomal dominant AS (ADAS). Patients with minimal change disease (MCD) were recruited as controls. Microarray analysis was carried out on isolated glomeruli from the patients and validated. Then, corresponding mutant human podocytes (p.C1616Y) and 129 mice (p.C1615Y, the murine homolog to the human p.C1616Y) were constructed. The highest differentially expressed genes (DEGs) from microarray analysis were validated in transgenic mice and podocytes before and after administration of MMP-2 inhibitor (SB-3CT) and NOX4 inhibitor (GKT137831). We further validated NOX4/MMP-2/apoptosis pathway by real-time polymerase chain reaction (PCR), immunohistochemistry, and western blot in renal tissues from the ADAS patients.
RESULTS
Using microarray analysis, we observed that DEGs, including NOX4/HO MMP-2, and podocyte apoptosis-related genes were significantly upregulated. These genes were validated by real-time PCR, histologic analysis, and western blot in corresponding mutant human podocyte (p.C1616Y) and/or mice models (p.C1615Y). Moreover, we found podocyte apoptosis was abrogated and MMP-2 expression was down-regulated both and by NOX4 inhibition, urinary albumin-to-creatinine ratio, 24-hour proteinuria; and renal pathologic lesion was attenuated by NOX4 inhibition . Furthermore, podocyte apoptosis was attenuated whereas NOX4 expression remained the same by inhibition of MMP-2 both and .
CONCLUSION
These results indicated that NOX4 might induce podocyte apoptosis through the regulation of MMP-2 in patients with mutations. Our findings provided new insights into the mechanism of ADAS.
PubMed: 37705901
DOI: 10.1016/j.ekir.2023.06.007 -
IScience Oct 2023Diabetes mellitus and alterations in thyroid hormone (TH) signaling are closely linked. Though the role of TH signaling in cell differentiation and growth is well known,...
Diabetes mellitus and alterations in thyroid hormone (TH) signaling are closely linked. Though the role of TH signaling in cell differentiation and growth is well known, it remains unclear whether its alterations contribute to the pathobiology of diabetic cells. Here, we aim to investigate whether the administration of exogenous T3 can counteract the cellular remodeling that occurs in diabetic cardiomyocytes, podocytes, and pancreatic beta cells. Treating diabetic rats with T3 prevents dedifferentiation, pathological growth, and ultrastructural alterations in podocytes and cardiomyocytes. , T3 reverses glucose-induced growth in human podocytes and cardiomyocytes, restores cardiomyocyte cytoarchitecture, and reverses pathological alterations in kidney and cardiac organoids. Finally, T3 treatment counteracts glucose-induced transdifferentiation, cell growth, and loss in pancreatic beta cells through TH receptor alpha1 activation. Our studies indicate that TH signaling activation substantially counteracts diabetes-induced pathological remodeling, and provide a potential therapeutic approach for the treatment of diabetes and its complications.
PubMed: 37752946
DOI: 10.1016/j.isci.2023.107826 -
Glomerular Diseases 2023Minimal change disease and primary FSGS are podocytopathies but are also immune-mediated diseases. Rituximab acts via multiple mechanisms by tilting the balance between... (Review)
Review
BACKGROUND
Minimal change disease and primary FSGS are podocytopathies but are also immune-mediated diseases. Rituximab acts via multiple mechanisms by tilting the balance between autoreactive B and T cells in favor of regulatory B and T cells. The consequences are decreased production of cytokines, chemokines, and permeability factors by these cells. In the past decade, we have seen the discovery of autoantibodies mediating nephrotic syndrome (anti-annexin A2 antibody, anti-UCHL1 antibody, and anti-nephrin antibody), and rituximab decreases their production. Rituximab also binds to podocyte SMPDL3b and has direct podocyte actions.
SUMMARY
Rituximab's role in managing these primary podocytopathies has been discussed in this brief review. Rituximab has been used extensively in children and adults with frequently relapsing and steroid-dependent nephrotic syndrome. However, rituximab is not very promising in adult steroid-resistant nephrotic syndrome. Although ofatumumab would cause prolonged B-cell depletion and is fully humanized, it is unclear if it is superior to rituximab in preventing relapse of nephrotic syndrome.
KEY MESSAGES
Rituximab therapy can induce prolonged remission in adults with frequently relapsing and steroid-dependent nephrotic syndrome. However, no good data exist on using rituximab in steroid-resistant nephrotic syndrome.
PubMed: 37901702
DOI: 10.1159/000533695 -
The Journal of Clinical Investigation Jan 2024Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic...
Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which G1 and G2 cause kidney disease is poorly understood. Here, we leveraged 3 experimental models and a recently reported small molecule blocker of APOL1 protein, VX-147, to identify the upstream mechanism of G1-induced cytotoxicity. In HEK293 cells, we demonstrated that G1-mediated Na+ import/K+ efflux triggered activation of GPCR/IP3-mediated calcium release from the ER, impaired mitochondrial ATP production, and impaired translation, which were all reversed by VX-147. In human urine-derived podocyte-like epithelial cells (HUPECs), we demonstrated that G1 caused cytotoxicity that was again reversible by VX-147. Finally, in podocytes isolated from APOL1 G1 transgenic mice, we showed that IFN-γ-mediated induction of G1 caused K+ efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147. Together, these results establish APOL1-mediated Na+/K+ transport as the proximal driver of APOL1-mediated kidney disease.
Topics: Mice; Animals; Humans; Apolipoprotein L1; HEK293 Cells; Genetic Variation; Kidney Diseases; Mice, Transgenic; Organothiophosphorus Compounds
PubMed: 38227370
DOI: 10.1172/JCI172262 -
Med (New York, N.Y.) Nov 2023Shiga toxin (Stx)-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) is the leading cause of acute kidney injury in children, with an associated mortality...
BACKGROUND
Shiga toxin (Stx)-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) is the leading cause of acute kidney injury in children, with an associated mortality of up to 5%. The mechanisms underlying STEC-HUS and why the glomerular microvasculature is so susceptible to injury following systemic Stx infection are unclear.
METHODS
Transgenic mice were engineered to express the Stx receptor (Gb3) exclusively in their kidney podocytes (Pod-Gb3) and challenged with systemic Stx. Human glomerular cell models and kidney biopsies from patients with STEC-HUS were also studied.
FINDINGS
Stx-challenged Pod-Gb3 mice developed STEC-HUS. This was mediated by a reduction in podocyte vascular endothelial growth factor A (VEGF-A), which led to loss of glomerular endothelial cell (GEnC) glycocalyx, a reduction in GEnC inhibitory complement factor H binding, and local activation of the complement pathway. Early therapeutic inhibition of the terminal complement pathway with a C5 inhibitor rescued this podocyte-driven, Stx-induced HUS phenotype.
CONCLUSIONS
This study potentially explains why systemic Stx exposure targets the glomerulus and supports the early use of terminal complement pathway inhibition in this devastating disease.
FUNDING
This work was supported by the UK Medical Research Council (MRC) (grant nos. G0901987 and MR/K010492/1) and Kidney Research UK (grant nos. TF_007_20151127, RP42/2012, and SP/FSGS1/2013). The Mary Lyon Center is part of the MRC Harwell Institute and is funded by the MRC (A410).
Topics: Child; Humans; Mice; Animals; Podocytes; Shiga Toxin; Vascular Endothelial Growth Factor A; Escherichia coli Infections; Hemolytic-Uremic Syndrome; Shiga-Toxigenic Escherichia coli; Complement Activation; Kidney Diseases
PubMed: 37863058
DOI: 10.1016/j.medj.2023.09.002 -
Cells Oct 2023Calcineurin inhibitors (CNI) can suppress allo- and autoimmunity by suppressing T cell function but also have anti-proteinuric effects by stabilizing the cellular... (Review)
Review
Calcineurin inhibitors (CNI) can suppress allo- and autoimmunity by suppressing T cell function but also have anti-proteinuric effects by stabilizing the cellular components of the kidney's filtration barrier. Therefore, CNI are used in autoimmune kidney diseases with proteinuria. However, the traditional CNI, cyclosporine A and tacrolimus, have a narrow therapeutic range, need monitoring of drug levels, and their use is associated with nephrotoxicity and metabolic alterations. Voclosporin (VOC), a novel CNI, no longer requires drug level monitoring and seems to lack these adverse effects, although hypertension and drug-drug interactions still occur. VOC demonstrated efficacy superior to standard-of-care in controlling active lupus nephritis in the phase 2 AURA-LV and the phase 3 AURORA-1 trials and was approved for the treatment of active lupus nephritis. However, how to implement VOC into the current and changing treatment landscape of lupus nephritis is still debated. Here, we review the unique chemistry, pharmacology, and toxicity profile of VOC, summarize the efficacy and safety data from the AURA-LV and AURORA-1 trials, and discuss the following four possible options to implement VOC into the management of lupus nephritis, namely regarding B cell-targeting therapy with belimumab (BEL). These include: 1. patient stratification to either VOC or BEL, 2. VOC/BEL combination therapy, 3. VOC-BEL sequential therapy, or 4. alternative options for the rapid antiproteinuric effect of VOC.
Topics: Humans; Calcineurin Inhibitors; Cyclosporine; Lupus Nephritis
PubMed: 37887284
DOI: 10.3390/cells12202440 -
Pharmacological Research Dec 2023Although hyperhomocysteinemia (hHcys) has been recognized as an important independent risk factor in the progression of end-stage renal disease and the development of...
Although hyperhomocysteinemia (hHcys) has been recognized as an important independent risk factor in the progression of end-stage renal disease and the development of cardiovascular complications related to end-stage renal disease, the mechanisms triggering pathogenic actions of hHcys are not fully understood. The present study was mainly designed to investigate the role of HDACs in renal injury induced by hHcys. Firstly, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC9 was preferentially upregulated in the kidney from mice with hHcys. Deficiency or pharmacological inhibition of HDAC9 ameliorated renal injury in mice with hHcys. Moreover, podocyte-specific deletion of HDAC9 significantly attenuated podocyte injury and proteinuria. In vitro, gene silencing of HDAC9 attenuated podocyte injury by inhibiting apoptosis, reducing oxidative stress and maintaining the expressions of podocyte slit diaphragm proteins. Mechanically, we proved for the first time that HDAC9 reduced the acetylation level of H3K9 in the promoter of Klotho, then inhibited gene transcription of Klotho, finally aggravating podocyte injury in hHcys. In conclusion, our results indicated that targeting of HDAC9 might be an attractive therapeutic strategy for the treatment of renal injury induced by hHcys.
Topics: Animals; Mice; Epigenetic Repression; Histone Deacetylases; Hyperhomocysteinemia; Kidney Failure, Chronic; Podocytes
PubMed: 37995896
DOI: 10.1016/j.phrs.2023.107009 -
Annals of Medicine Dec 2024Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, causing a substantive threat to the public, which receives global concern. However, there are... (Review)
Review
Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, causing a substantive threat to the public, which receives global concern. However, there are limited drugs targeting the treatment of DN. Owing to this, it is highly crucial to investigate the pathogenesis and potential therapeutic targets of DN. The process of ferroptosis is a type of regulated cell death (RCD) involving the presence of iron, distinct from autophagy, apoptosis, and pyroptosis. A primary mechanism of ferroptosis is associated with iron metabolism, lipid metabolism, and the accumulation of ROS. Recently, many studies testified to the significance of ferroptosis in kidney tissue under diabetic conditions and explored the drugs targeting ferroptosis in DN therapy. Our review summarized the most current studies between ferroptosis and DN, along with investigating the significant processes of ferroptosis in different kidney cells, providing a novel target treatment option for DN.
Topics: Humans; Diabetic Nephropathies; Ferroptosis; Iron; Kidney; Lipid Metabolism; Reactive Oxygen Species
PubMed: 38657163
DOI: 10.1080/07853890.2024.2346543 -
Life (Basel, Switzerland) Oct 2023Renal involvement and kidney injury are common in COVID-19 patients, and the symptoms are more severe if the patient already has renal impairment. Renal involvement in... (Review)
Review
Renal involvement and kidney injury are common in COVID-19 patients, and the symptoms are more severe if the patient already has renal impairment. Renal involvement in COVID-19 is multifactorial, and the renal tubule is mainly affected, along with podocyte injury during SARS-CoV-2 infection. Inflammation, complement activation, hypercoagulation, and crosstalk between the kidney and lungs, brain, and heart are contributory factors. Kidney injury during the acute phase, termed acute kidney injury (AKI), may proceed to chronic kidney disease if the patient is discharged with renal impairment. Both AKI and chronic kidney disease (CKD) increase mortality in COVID-19 patients. Further, COVID-19 infection in patients suffering from CKD is more severe and increases the mortality rate. Thus, it is important to address both categories of patients, either developing AKI or CKD after COVID-19 or previously having CKD, with proper management and treatment. This review discusses the pathophysiology involved in AKI and CKD in COVID-19 infection, followed by management and treatment of AKI and CKD. This is followed by a discussion of the importance of screening and treatment of CKD patients infected with COVID-19 and future perspectives to improve treatment in such patients.
PubMed: 38004277
DOI: 10.3390/life13112137