Effects of periostin deficiency on kidney aging and lipid metabolism

Abstract

Periostin plays a crucial role in fibrosis, which is involved in kidney aging. A few studies have shown that lipid metabolism is involved in kidney aging. We investigated the role of periostin in lipid metabolism during kidney aging. Renal function, fibrosis, and inflammatory markers were studied using urine, blood, and tissue samples from wild-type (WT) C57BL/6 mice and Postn-null mice of 2 and 24 months of age. Lipids were quantitatively profiled using liquid chromatography-tandem mass spectrometry in the multiple reaction monitoring mode. Renal function was worse and tubular atrophy/interstitial fibrosis, periostin expression, and inflammatory and fibrotic markers were more severe in aged WT mice than in young WT mice. In aged Postn-null mice, these changes were mitigated. Thirty-five differentially regulated lipids were identified. Phosphatidylcholines, cholesteryl ester, cholesterol, ceramide-1-phosphate, and CCL5 expression were significantly higher in aged WT mice than in aged Postn-null mice. Particularly, linoleic acid, linolenic acid, arachidonic acid, and docosahexaenoic acid differed strongly between the two groups. Lysophosphatidylcholine acyltransferase 2, which converts lysophosphatidylcholine to phosphatidylcholine, was significantly higher in aged WT mice than in aged Postn-null mice. Periostin expression in the kidneys increased with age, and periostin ablation delayed aging. Changes in lipids and their metabolism were found in Postn-null mice. Further research on the precise mechanisms of and relationships between lipid expression and metabolism, kidney aging, and periostin expression is warranted.

Keywords: aging; kidney; lipid; lipidomics; periostin.

Figure 1

Gross appearance and renal function in young and aged WT and Postn-null mice. (A) Aged Postn-null mice had smaller body and kidney sizes than aged WT mice. Representative data are shown (N = 7/group) (bar: 1 cm). Data are the mean ± SEM. *p < 0.05 (unpaired t-test). (B) Albuminuria and serum creatinine were reduced in aged Postn-null mice. Data are the mean ± SEM. *p < 0.05 (unpaired t-test). (C) There was no difference in the survival rate between aged Postn-null mice and aged WT mice.

Figure 2

Role of periostin in renal fibrosis due to aging. (A) Tubular atrophy, interstitial fibrosis, glomerular sclerosis, and periostin expression were increased in aged WT mice, but not so much in aged Postn-null mice. Representative data are shown (N = 7/group). Magnification: 40× (top); 400× (bottom); 200× (bottom). Data are the mean ± SEM. ***p < 0.001 (unpaired t-test). (B) Beta-galactosidase expression was increased in aged WT mice, but a lesser extent in aged Postn-null mice. Representative data are shown (N = 7/group). Magnification: 40× (top); 200× (bottom). Data are the mean ± SEM. ***p < 0.001 (unpaired t-test). (C) Apoptotic cells were significantly increased in aged WT, but to a markedly lower level in aged Postn-null mice. Data are the mean ± SEM. ***p < 0.001 (unpaired t-test). (D) The expression of fibrosis markers was increased in aged WT mice, but not so much in aged Postn-null mice. Data are the mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001 (unpaired t-test).

Figure 3

Overall lipid profiles according to kidney age and periostin expression. (A) Numbers of lipids identified. In total, 430 lipid species of 17 classes were identified. The volcano plot shows the magnitude and significance of the fold changes in young WT mice group (middle) and aged Postn-null mice (right) versus aged WT mice. The two vertical red lines indicate the |1.5|-fold change, and the horizontal line indicates a p-value of 0.05. Red dots are DRLs. (B) Clustering heatmap of the 430 lipids identified. (C) Lipid levels per class in the four study groups. Data are the mean ± SEM. Statistical significance was evaluated using Tukey tests. *p < 0.05; **p < 0.01; ***p < 0.001.

Figure 4

Changes in lipid profiles according to kidney age and periostin expression. (A) chE and cholesterol were significantly increased in aged WT mice compared to young mice, but to a lesser extent in aged Postn-null mice. Data are the mean ± SEM. *p < 0.05 (unpaired t-test); ***p < 0.001 (unpaired t-test). (B, C) SM and Cer did not differ between the groups, but C1P was higher in aged WT mice than in aged Postn-null mice. Data are the mean ± SEM. **p < 0.01 (unpaired t-test). (D) LPC was increased in all aged mice, with no difference between WT mice and Postn-null mice. In contrast, PC was significantly lower in aged Postn-null mice than in aged WT mice. Data are the mean ± SEM. **p < 0.01 (unpaired t-test).

Figure 5

(A) SREBP1 and ABCA1 protein expression levels. Data are the mean ± SEM. **p < 0.01 (unpaired t-test). (B) Protein-protein interaction network of periostin and important factors in aging. Pathways are indicated by dotted lines based on clustering of the proteins according to their biological processes using STRING. ABCA1, ATP binding cassette transporter 1; AKT1, AKT Serine/Threonine Kinase 1; CCL5, C-C Motif Chemokine Ligand 5; CDH1, Cadherin 1; CERK, Ceramide Kinase; COL1A2, Collagen Type I Alpha 2 Chain; FN1, Fibronectin 1; HMGCR, 3-Hydroxy-3-Methylglutaryl-CoA Reductase; HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2; PLA2G4A, Phospholipase A2 Group IVA; POSTN, Periostin; SLC2A2, Solute Carrier Family 2 Member 2; SMPD2, Sphingomyelin Phosphodiesterase 2; SREBF1, Sterol Regulatory Element Binding Transcription Factor 1; TGF, Transforming growth factor.