Vitamin D Activates miR-126a-5p to Target GSK-3ß and Alleviates Systemic Lupus Erythematosus in MRL/LPR Mice.

BACKGROUND: The etiology of systemic lupus erythematosus (SLE) is complex, and the disease is thus difficult to cure. In this regard, it has been established that SLE patients are characterized by differing levels of vitamin D-hydroxylation; however, the direct effects of vitamin D (VitD) in these patients remain unknown. OBJECTIVE: Therefore, we investigated the effects and mechanisms of action of VitD in the context of SLE. METHODS: The effects of VitD on MRL/LPR mice were studied by synthesizing glycogen synthase kinase-3ß (GSK-3ß)-interfering lentiviruses and transfecting with miR-126a-5p mimics. Changes in the body weight of mice were recorded for 6 weeks. Western blotting was performed to determine the levels of T-bet, GATA3, and GSK-3ß protein expression, and qRT-PCR was performed to determine the levels of miR-126a-5p and GSK-3ß mRNA expression. ELISA was performed to determine the levels of ANA, dsDNA, and snRNP/Sm in mice serum. RESULTS: GSK-3ß and miR-126a-5p were expressed at high and low levels, respectively, in MRL/LPR mice. VitD (30 ng/kg) was found to reduce the expression of GSK-3ß and increase miR-126a-5p expression, which targets GSK-3ß. T-bet and GATA3 were found to be positively regulated by miR-126a-5p and VitD and negatively regulated by GSK-3ß. The body weight of mice was not altered by VitD. ANA, dsDNA, and snRNP/Sm were positively regulated by miR- 126a-5p and VitD and negatively regulated by GSK-3ß. The effects of GSK-3ß were enhanced in response to the inhibition of miR-126a-5p expression. CONCLUSION: VitD upregulated miR-126a-5p to target GSK-3ß expression, thereby alleviating the SLE in MRL/LPR mice.

Twenty-three-year review of disease patterns from renal biopsies: an experience from a pediatric renal center.

BACKGROUND: The aim of this study was to investigate the clinical and pathological characteristics as well as their associations with trends for diseases in 1,579 pediatric renal biopsies from 1989 to 2012. METHODS: The clinical and pathological data were retrospectively analyzed for children undergoing renal biopsy from 1989 to 2012 in our hospital. RESULTS: Primary glomerulonephritis (PGN) accounted for 60.1% of total cases, followed by secondary glomerulonephritis (SGN) (31.2%) and hereditary nephropathy (8.3%). The major clinical patterns of PGN and SGN were nephritic syndrome (NS) and Henoch-Schönlein purpura nephritis (HSPN), respectively. Minimal change disease/mild disease (MCD/ML), IgAN and mesangial proliferative glomerulonephritis (MsPGN) were the most common pathological patterns of PGN. Male patients were most likely to suffer from NS, HBV-associated glomerulonephritis (HBVGN) or Alport syndrome, while females were most likely to suffer from isolated hematuria, rapidly progressive glomerulonephritis (RPGN), lupus nephritis (LN), ANCA-associated glomerulonephritis or thin basement membrane disease. The proportions of NS, isolated hematuria, acute nephritic syndrome, chronic nephritic syndrome, HBVGN, LN and hemolytic uremic syndrome changed significantly with aging. The clinical patterns of PGN were significantly correlated with the distribution of pathological types: MCD/ML and IgMN presented most often as NS; MCD/ML and IgAN presented most often as isolated hematuria; IgAN and MsPGN presented most often as hematuria with proteinuria. The spectrum of NS, HSPN, HBVGN and IgAN changed during the 23 years, and the percentage of repeated renal biopsies was low (1.2%) in pediatric cases with kidney disease. CONCLUSIONS: Glomerular diseases in children are closely related to age and sex of patient. The spectrum of kidney diseases from our center has changed significantly over the last 23 years.

1,25-Dihydroxyvitamin D3 ameliorates podocytopenia in rats with adriamycin-induced nephropathy.

OBJECTIVE: To investigate the role of α3ß1 integrin and α/ß-dystroglycan in protective effects of 1,25(OH)2D3 on podocytes in rats with adriamycin-induced nephropathy. METHODS: Sprague-Dawley rats were randomly divided into three groups: control group (NC), nephropathy group (NE), and nephropathy+1,25(OH)2D3 group (ND). Rats in NE and ND group were injected intravenously with adriamycin (0.1 mg/10 g body weight) to induce nephropathy, and those in ND group were then subcutaneously treated with 1,25(OH)2D3 for 8 weeks. Urinary protein level, number of urine podocytes, foot process width and glomerulosclerotic index were determined. Nephrin and podocin mRNA and protein expressions were determined by RT-PCR and western blot, respectively. Podocyte density and expressions of α3ß1 integrin and α/ß-dystroglycan (DG) were analyzed by immunohistochemistry and western blot, respectively. RESULTS: The increase in proteinuria, podocyturia and width of foot process in NE group were ameliorated after treatment with 1,25(OH)2D3 for 8 weeks. The glomerulosclerotic index was significantly decreased in ND group when compared with NE group. The podocyte density in ND group (10.3±1.64 cells/glomerulus) was significantly higher than that in NE group (8.43±1.75 cells/glomerulus) (p=0.008). 1,25(OH)2D3 treatment could significantly up-regulate the mRNA and protein expressions of nephrin and podocin, and the protein expressions of α3ß1 integrin and α/ß-DG. CONCLUSION: The expressions of nephrin, podocin, α3ß1 integrin and α/ß-DG were decreased in rats with nephropathy. However, 1,25(OH)2D3 treatment could significantly up-regulate the expressions of nephrin, podocin, α3ß1 integrin and α/ß-DG proteins which might suppress podocyte detachment and podocytopenia.

1, 25-dihydroxyvitamin D3 decreases adriamycin-induced podocyte apoptosis and loss.

BACKGROUND: Selective proteinuria is frequently observed in glomerular diseases characterized by podocyte injury. Although, 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D(3)] has potential therapeutic effects on chronic kidney diseases through decreasing podocyte loss, the mechanism underlying the beneficial effects of 1,25(OH)(2)D(3) on podocytes remains still unknown. The present study tested the hypothesis that 1,25(OH)(2)D(3) directly reduced podocyte apoptosis and loss. METHODS: Sprague-Dawley (SD) rats were randomly assigned into three groups: Adriamycin (ADR) group (n=15), ADR+1,25-(OH)(2)D(3) group (n=16), and control group (n=16). Rats in ADR+1,25-(OH)(2)D(3) group were treated with 1,25(OH)(2)D(3) for 8 weeks. The number of podocytes and foot process width (FPW) were detected by transmission electron microscopy. The number of apoptotic podocytes per glomerulus and that of apoptotic nuclei and caspase-3 activity in cultured podocytes were determined by TUNEL staining. The average number of podocytes per glomerulus was quantified by immunohistochemistry. Expressions of p-Smad2/3, p-Smad1/5/8, Fas, Fas-Associated protein with Death Domain (FADD), Bax, and Bcl-2 proteins were examined by Western blot assay. RESULTS: Compared with control group, proteinuria, FPW, apoptotic podocytes, caspase-3 activity, the protein expressions of p-Smad2/3, Fas, FADD, and Bax were significantly increased, podocyte density, p-Smad1/5/8 and Bcl-2 expression were decreased in ADR group. 1,25(OH)(2)D(3) significantly reduced proteinuria, FPW, caspase-3 activity, expressions of p-Smad2/3, Fas, FADD, and Bax and apoptosis of podocytes, but increased serum albumin, number of viable podocytes , p-Smad1/5/8 and Bcl-2 expression in ADR treated rats. CONCLUSION: ADR-induced podocyte apoptosis was associated with the imbalance of p-Smad2/3, p-Smad1/5/8 the activity of caspase-3 and aberrant expressions of, Fas, FADD, Bax and Bcl-2. The beneficial effects of 1,25(OH)(2)D(3 )on podocytes may be attributable to inhibit podocyte apoptosis and the amelioration of podocytopenia.