The role of extracellular vesicles in podocyte autophagy in kidney disease.

Podocytes are the key cells involved in protein filtration in the glomerulus. Once proteins appear in the urine when podocytes fail, patients will end with renal failure due to the progression of glomerular damage if no proper treatment is applied. The injury and loss of podocytes can be attributed to diverse factors, such as genetic, immunologic, toxic, or metabolic disorders. Recently, autophagy has emerged as a key mechanism to eliminate the unwanted cytoplasmic materials and to prolong the lifespan of podocytes by alleviating cell damage and stress. Typically, the fundamental function of extracellular vesicles (EVs) is to mediate the intercellular communication. Recent studies have suggested that, EVs, especially exosomes, play a certain role in information transfer by communicating proteins, mRNAs, and microRNAs with recipient cells. Under physiological and pathological conditions, EVs assist in the bioinformation interchange between kidneys and other organs. It is suggested that EVs are related to the pathogenesis of acute kidney injury and chronic kidney disease, including glomerular disease, diabetic nephropathy, renal fibrosis and end-stage renal disease. However, the role of EVs in podocyte autophagy remains unclear so far. Here, this study integrated the existing information about the relevancy, diagnostic value and therapeutic potential of EVs in a variety of podocytes-related diseases. The accumulating evidence highlighted that autophagy played a critical role in the homeostasis of podocytes in glomerular disease.

Early-onset COQ8B (ADCK4) glomerulopathy in a child with isolated proteinuria: a case report and literature review.

BACKGROUND: Herein, a 3-year-old boy presented with hidden-onset isolated proteinuria was reported. The disease was induced by COQ8B (previously termed ADCK4) compound heterozygous variants, including c.[271C > T] and c.[737G > A], which were inherited from his father and mother, respectively. CASE PRESENTATION: The patient visited our clinic due to non-nephrotic range proteinuria for 3 months, but no obvious abnormality was detected in the vital signs or laboratory test results. Renal histopathology revealed mitochondrial nephropathy, which manifested as mild glomerular abnormalities under light microscope, together with mitochondrial proliferation and hypertrophy and crowded arrangement under electron microscope. As suggested by whole exome sequencing, the patient inherited the COQ8B compound heterozygous variants from both of his parents who showed normal phenotype. After literature review, it was confirmed that one of the variant site (c.[271C > T]) had not been reported among the East Asian populations so far. CONCLUSIONS: Steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis are the most common phenotypes and renal histopathological manifestations of COQ8B variant. Nonetheless, our case shows that such variant may have hidden and mild clinical manifestations at the early onset. Therefore, early diagnosis will help to identify children at the early disease stage who have opportunity to benefit from oral coenzyme Q10 supplementation.

IL-17 aggravates renal injury by promoting podocyte injury in children with primary nephrotic syndrome.

Primary nephrotic syndrome (PNS) is the most common chronic kidney disease in childhood, where podocyte injury is a key factor in the occurrence of kidney disease. In the present study, the expression of IL-17 in renal tissues of patients with PNS and its relationship with podocyte injury were examined. Reverse transcription-quantitative PCR (RT-qPCR), western blot analysis and immunochemistry were used to measure the expression of IL-17 in renal biopsies of patients with ONS, including 9 patients with minimal change nephrotic syndrome (MCNS), 15 patients with mesangial proliferative glomerulonephritis (MsPGN) and 9 patients with focal segmental glomerulosclerosis (FSGS), in addition to 15 normal kidney tissues. IL-17 was found to be highly expressed in the renal tissues from patients with PNS, with the highest expression levels found in tissues from patients with FSGS and the lowest in those from MCNS. A negative correlation was observed between the levels of IL-17 mRNA and PCX mRNA in renal tissues, whereas a positive correlation between IL-17 mRNA levels and the number of urinary podocytes in patients with PNS was found. In vitro, IL-17 induced podocyte apoptosis and reduced the expression of markers associated with podocytes, including Wilm's tumor 1, nephrin, synaptopodin and podocalyxin, whilst increasing the levels of Fas, Fas ligand (FasL), active-caspase-8, active-caspase-3 and phosphorylated-p65. However, treatment with helenalin, a NF-κB inhibitor, decreased p65 phosphorylation, attenuated IL-17-induced podocyte apoptosis and suppressed the IL-17-activated Fas/FasL/caspase-8/caspase-3 apoptotic pathway. Taken together, these observations suggest that IL-17 was highly expressed in renal tissues from patients with PNS, where it induced podocyte apoptosis by activating the Fas/FasL/caspase-8/caspase-3 apoptotic pathway in a NF-κB-dependent manner.

Amelioration of Lipopolysaccharide-Induced Nephrotic Proteinuria by NFAT5 Depletion Involves Suppressed NF-κB Activity.

Idiopathic nephrotic syndrome (INS) is characterized by proteinuria, in which podocyte dysfunction associated with NF-κB-mediated inflammation plays an important role. The nuclear factor of activated T cells 5 (NFAT5) has been shown to enhance NF-κB activity. However, whether NFAT5 is associated with proteinuria remains uncharacterized. NFAT5 is upregulated in the glomeruli in lipopolysaccharide (LPS)-induced mouse nephrotic proteinuria, as well as in LPS-treated podocytes in vitro. In addition, NFAT5 depletion improves filtration barrier function of LPS-treated podocytes in vitro. Mechanistically, NFAT5 depletion suppresses NF-κB activation and downstream proinflammatory reaction in LPS-treated podocytes, and moreover, NF-κB inhibition improves filtration barrier function of LPS-treated podocytes, suggesting that the suppressed NF-κB activity at least partly accounts for NFAT5 depletion-improved filtration barrier function. Furthermore, in vivo, depletion of NFAT5 suppresses NF-κB activity and ameliorates nephrotic proteinuria in LPS-treated mice. These findings suggest a protective role of NFAT5 depletion against LPS-induced nephrotic proteinuria and relate it to the suppression of NF-κB activity.

Interleukin-7 stimulation inhibits nephrin activation and induces podocyte injury.

The glomerular podocytes control filtration barrier permeability in the kidney, and their disturbance underlies the pathogenesis of idiopathic nephrotic syndrome (INS), a kidney disease that predominantly occurs in children. In this study, we found that the interleukin-7 receptor (IL-7R) was induced in the glomeruli of adriamycin (ADR)-induced mouse nephropathy, a rodent model of nephrotic syndrome. In addition, IL-7R was also induced by ADR in mouse podocytes cultured in vitro. Functionally, we discovered that IL-7R activation through the stimulation of recombinant IL-7 induced apoptosis of podocytes, and moreover, IL-7 stimulation inhibited nephrin activation and caused actin cytoskeleton disorganization, indicating that IL-7 stimulation induces podocyte injury. Furthermore, IL-7 stimulation impaired the filtration barrier function of podocyte monolayer. Together, these results identify IL-7 and its receptor IL-7R as potential regulators of podocyte function, which might offer a novel therapeutic target in the treatment of INS.

New PAX2 heterozygous mutation in a child with chronic kidney disease: a case report and review of the literature.

BACKGROUND: We herein report a 3-year-old boy presented with chronic kidney disease (CKD) due to PAX2 missense mutation (C to G transversion at position 418 in exon 4). CASE PRESENTATION: He attended our clinic with a 3-month history of foamy urine. Upon examination, he had reduced estimated glomerular filtration rate (GFR) and renal atrophy. Genetic investigations revealed that he has inherited a mutated PAX2 gene from his father, who had renal failure at the age of 20. We searched the literature and confirmed that this mutation site has not been reported by any other group before. CONCLUSIONS: Although renal coloboma syndrome (RCS) with simultaneous kidney and eye involvement is the most common phenotype of PAX2 mutations, current literature supports that such mutations may have profuse clinical manifestations and renal hypoplasia is one distinct entity in the spectrum.

Kawasaki disease in two sets of monozygotic twins: Is the etiology genetic or environmental?

Two sets of monozygotic (MZ) twins with Kawasaki disease (KD) from two different families are reported. Twin set 1, previously healthy 71-day-old MZ twin girls were diagnosed with incomplete KD and pneumonia. The symptoms occurred at the same time in both girls. Both girls had ectasia of right coronary arteries. In twin set 2, the younger of 18-month-old MZ twin boys was diagnosed with KD and bronchitis. After 53 days, his elder brother was diagnosed with the same disease. The symptoms occurred at different time, but were almost identical. Neither boy displayed coronary artery changes. These findings support the hypothesis that genes susceptible to KD and coronary-artery lesions may exist in families. The different clinical characteristics among MZ twins from different families also suggest diverse and complex nature of KD.

Multiple organ dysfunction syndrome associated with Mycoplasma pneumoniae infection

In this study, we report one case of a three-year-old boy infected with Mycoplasma pneumonia (MP) and presenting concomitant multiple organ damage of the heart, kidney, lung and liver, among others, together with a brief review for the diagnosis and treatment of MP infection with multiple organ dysfunction syndrome (MODS).

Multiple organ dysfunction syndrome associated with Mycoplasma pneumoniae infection.

In this study, we report one case of a three-year-old boy infected with Mycoplasma pneumonia (MP) and presenting concomitant multiple organ damage of the heart, kidney, lung and liver, among others, together with a brief review for the diagnosis and treatment of MP infection with multiple organ dysfunction syndrome (MODS).

[Clinical analysis of 68 cases of childhood dilated cardiomyopathy].

OBJECTIVE: To study the ECG features in children with dilated cardiomyopathy (DCM), and related factors for the occurrence of arrhythmia secondary to DCM. METHODS: Data from 68 children with DCM from January 1998 to March 2011 were studied. The children were classified into three groups: severe arrhythmia (n=42), non-severe arrhythmia (n=20) and non-arrhythmia (n=6). Left ventricular end diastolic diameter (LVED), left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were compared. RESULTS: Abnormal ECG results were found in all of the 68 children with DCM. Sinus tachycardia (91%) and ectopic pulsatile (86%) were common. LVED in the severe arrhythmia group (74±6 mm) was greater than that in the non-severe arrhythmia group (65±4 mm; P<0.05) and non-arrhythmia group (61±3 mm; P<0.05). LVED in the non-severe arrhythmia group was also greater than that in the non-arrhythmia group (P<0.05). LVEF and LVFS in the severe arrhythmia group were (30±11)% and (22±4)%, respectively, which were lower than those in the non-severe arrhythmia groupï¼»(37±12)% and (28±5)%, respectivelyï¼½and non-arrhythmia groupï¼»(45±9)% and (34±7)%, respectivelyï¼½(P<0.05). There were also significant differences in the LVEF and LVFS between the non-severe arrhythmia and non-arrhythmia groups (P<0.05). CONCLUSIONS: The common abnormal ECG findings are sinus tachycardia and ectopic pulsatile in children with DCM. Arrhythmia is one of the main clinical manifestations of DCM. The occurrence of arrhythmia is associated with the left ventricular size and heart function.

[Experimental study on expression of connective tissue growth factor in viral myocarditis in mice].

OBJECTIVE: To study the expression of connective tissue growth factor (CTGF) in the myocardial tissue of mice with viral myocarditis (VMC). METHOD: Balb/c mice were infected with coxsackie virus B3 (CVB3) to establish VMC model. The mice were divided into control group (n = 50) and VMC group (n = 50). on days 4, 7, 14 and 21 after infection, heart specimens of 8 mice were randomly taken and examined after HE staining for myocardial necrosis and cellular infiltration. The area of positive Masson stained myocardium collagen fibers was measured, and collagen volume fraction (CVF) was measured. Then the level of serum creatine phosphokinase-MB (CKMB) was determined. The levels of CTGF and TGF-ß1 were detected by streptavidin peroxidase immunoperoxidase technique. Expression of CTGF and TGF-ß1 were detected with reverse transcription-polymerase chain reaction (RT-PCR). At the same time, the correlations were analyzed. RESULT: (1) The level of CKMB peaked on day 7, and decreased afterwards (455.45 ± 37.95, 606.95 ± 35.64, 573.62 ± 42.90, 308.60 ± 20.49, respectively, 4 - 21 d points), in which 4, 7, 14 d points, there was significant difference compared with control group (t = 6.144, 12.558, 11.182, respectively, P < 0.01). (2) CVF increased significantly on day 14 (8.22 ± 1.95, t = 4.486, P < 0.01) and day 21 (9.46 ± 1.87, t = 4.486, P < 0.01) in VMC group. (3) Measured by streptavidin peroxidase immunoperoxidase technique, the levels of CTGF (171.50 ± 10.25, 141.70 ± 10.863, 110.35 ± 11.051, 81.05 ± 10.190, respectively, 4 - 21 d points) and TGF-ß1 (184.90 ± 11.480, 150.25 ± 9.915, 103.50 ± 10.455, 84.15 ± 9.848, respectively, 4 - 21 d points) increased after day 4 in VMC (P < 0.01). (4) Measured by RT-PCR, the expression of CTGF mRNA and TGF-ß1 increased in VMC group, and the increase was enhanced with the disease development (P < 0.01). (5) The expression of CTGF and TGF-ß1 was positively linearly correlated (r = 0.987, P < 0.01), the expression of CTGF was negatively correlated with CVF (r = -0.901, P < 0.01), but the expression of CTGF was detected earlier than myocardial fibrosis. CONCLUSION: The increase of CTGF expression was associated with the severity of myocardial fibrosis in VMC. These results suggest that abnormal expression of CTGF may take part in the development of fibrosis in VMC.