Angiopoietin-like protein 4 promotes hyperlipidemia-induced renal injury by down-regulating the expression of ACTN4.

OBJECTIVE: The molecular mechanism of in hyperlipidemia-induced renal injury has not been elucidated. Angiogenin-like protein 4 (ANGPTL4) is a key regulator of lipid metabolism. The role of ANGPTL4 hyperlipidemia-induced renal injury has not been reported. METHODS: Wild type C57 mice and gene angptl4 knockout mice were fed with 60% high fat diet or normal diet respectively. The serum lipid, urinary albumin and renal pathology were tested at the 9th, 13th, 17th and 21st week with high fat diet. RESULTS: Elevated blood lipids in the wild-type mice with high-fat diet were found at 9th week. At the 17th week, the level of urinary albumin in high-fat fed wild type mice were significantly higher than which with normal diet, correspondingly, segmental fusion of podocyte foot process in kidney could be observed in these hyperlipidemia mice. IHC showed that the expression of ANGPTL4 in glomeruli of high-fat fed wild type mice began significant elevated since the 9th week. When given high fat diet, compared to the wild type, the gene angptl4 knockout mice showed significantly alleviated the levels of hyperlipidemia, proteinuria and effacement of podocyte foot process. Finally, the expression of ACTN4 showed remarkably lower in glomeruli podocyte of wild type mice fed high fat diet than that of wild type mice with normal diet at each time-point (P < 0.01). Differently, the expression of ACTN4 in gene angptl4 knockout mice did not happen significantly weaken when given the same dose of high fat diet. CONCLUSION: ANGPTL4 could play a role in hyperlipidemic-induced renal injury via down-regulating the expression of ACTN4 in kidney podocyte.

ANGPTL3 impacts proteinuria and hyperlipidemia in primary nephrotic syndrome.

BACKGROUND: It is unclear why primary nephrotic syndrome (PNS) patients often have dyslipidemia. Recent studies have shown that angiopoietin-like protein 3 (ANGPTL3) is an important regulator of lipid metabolism. In this study, we explored how ANGPTL3 impacts dyslipidemia during PNS development. METHODS: We measured the serum levels of ANGPTL3 in PNS patients (n=196). Furthermore, the degree of proteinuria and lipid metabolism were examined in angptl3-overexpressing transgenic (angptl3-tg) mice at different ages. Moreover, in this study, we used the clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) system to create angptl3-knockout (angptl3-/-) mice to investigate lipopolysaccharide (LPS)-induced nephrosis. RESULTS: Compared with that in the healthy group, the serum level of ANGPTL3 in the PNS group was significantly increased (32 (26.35-39.66) ng/ml vs. 70.44 (63.95-76.51) ng/ml, Z =-4.81, P < 0.001). There were significant correlations between the serum level of ANGPTL3 and the levels of cholesterol (r=0.34, P < 0.001), triglycerides (r= 0.25, P = 0.001) and low-density lipoprotein (r= 0.50, P < 0.001) in PNS patients. With increasing age, angptl3-tg mice exhibited increasingly severe hypertriglyceridemia and proteinuria. The pathological features of angptl3-tg mice included rich lipid droplet deposition in hepatocytes and diffuse podocyte effacement. Compared to wild-type mice, angptl3-/- mice showed significantly lower degrees of lipid dysfunction and proteinuria after stimulation with LPS. The effects of ANGPTL3 on nephrotic dyslipidemia were confirmed in cultured hepatocytes subjected to angptl3 knockdown or overexpression. Finally, significant alterations in lipoprotein lipase (LPL) levels were observed in liver tissues from Angptl3-/- and wild-type mice stimulated with LPS. CONCLUSIONS: ANGPTL3 could be involved in the development of dyslipidemia, as well as proteinuria, during PNS pathogenesis. Inhibition of LPL expression may the mechanism by which ANGPTL3 induces hyperlipidemia in PNS.

Angiopoietin-like protein 3 markedly enhanced in the hyperlipidemia related proteinuria.

BACKGROUND: Angiopoietin-like protein 3(ANGPTL3) is well acknowledged as a key regulator of lipid metabolism. Now, there have not been enough data to explain the mechanism of hyperlipidemia related proteinuria. In this study, we hoped to investigate the changes of Angiopoietin-like protein 3(ANGPTL3) levels in hyperlipidemia patients with different proteinuria levels. METHODS: Seventy-one patients with hyperlipidemia were selected, who were hospitalized in Gansu Provincial People's Hospital from September 2016 to September 2017, and 20 healthy people in the physical examination center were selected. We combed through medical history and conducted clinical biochemical indicators of blood urea nitrogen (BUN), serum creatinine (SCr), 24 h urine protein quantitation (24hUPro), cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL) and low detection of density lipoproteins (LDL-C). The concentration of serum ANGPTL3 was measured by ELISA. RESULTS: 1. Serum ANGPTL3 in patients with hyperlipidemia related proteinuria was higher than that in the control group, and the difference was statistically significant (p < 0.05); 2. 24hUPro and BMI (r = 0.321, P = 0.002), TC (r = 0.465, P = 0.000), TG (r = 0.281, P = 0.007), LDL (r = 0.478, P = 0.000) in patients with hyperlipidemia related proteinuria are positively correlated, suggesting that dyslipidemia is related to the occurrence of proteinuria; 3. BMI, TC, TG and LDL in patients with hyperlipidemia related proteinuria were positively correlated with serum ANGPTL3. 4. The 24hUPro of patients with hyperlipidemia related proteinuria was positively correlated with serum ANGPTL3 levels, and BUN and SCr were not associated with serum ANGPTL3 level. 5. There was no significant difference in TC, TG, BMI, 24hUPro and serum ANGPTL3 between the statin-treated and the untreated groups in patients with hyperlipidemia related proteinuria. CONCLUSIONS: Angiopoietin-like protein 3 markedly enhanced in the hyperlipidemia related proteinuria.

Hepatitis B virus X protein decreases nephrin expression and induces podocyte apoptosis via activating STAT3.

The gene for hepatitis B virus X protein (HBx) comprises the smallest open reading frame in the HBV genome, and the protein product can activate various cell signaling pathways and regulate apoptosis, among other effects. However, in different cell types and under different external conditions, its mechanism of action differs. In the present study, the effect of HBx on the viability and apoptosis of mouse podocyte clone 5 (MPC5) cells was investigated. The cells were transfected with the HBx gene using pEX plasmid, and real-time quantitative PCR and western blot analysis were used to test the transfection efficiency and assess related protein expression. The highest expression of HBx occurred at 48 h after MPC5 cells were transfected with HBx. The expression of nephrin protein in the HBx transfection group was lower than that in blank and negative control groups. Following transfection of the HBx gene, podocyte viability was suppressed, while the rate of cell apoptosis was increased; moreover, the expression of signal transducer and activator of transcription 3 (STAT3) and phospho-STAT3 was increased compared with in the control groups. The present study suggests that STAT3 activation may be involved in the pathogenic mechanism of renal injuries caused by HBV injection. Thus STAT3 is a potential molecular target in the treatment of HBV-GN.