Inflammatory response and matrix metalloproteinases in chronic kidney failure: Modulation by adropin and spexin

Abstract

Chronic kidney disease is a major global public health problem. The peptide hormones adropin and spexin modulate many physiological functions such as energy balance and glucose, lipid and protein metabolism. However, it is unclear whether these peptides may exert effects on renal damage, tissue remodeling, and inflammatory conditions. In view of the limited information, we aimed to investigate the effect of adropin and spexin on matrix metalloproteinase and inflammatory response genes a rat model of adenine-induced chronic kidney failure. Chronic kidney failure was induced in rats by administering adenine hemisulfate. Renal function was determined in an autoanalyzer. Histopathological modifications were assessed by H&E staining. mRNA expression levels of ALOX 15, COX 1, COX 2, IL-1β, IL-10, IL-17A, IL-18 IL-21, IL-33, KIM-1, MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, NGAL, TGFβ1, TIMP-1, and TNFα in kidney tissue were measured by qPCR. Our results showed an increase of 24-h urine volume, serum creatinine, BUN, and urine protein levels in group with adenine-induced CKF. Adropin and spexin treatments decreased urine protein and 24-h urine volume. Renal damage, TIMP-1, IL-33, and MMP-2 increased after CKF induction, while COX 1, MMP-9, and MMP-13 levels were significantly reduced. Furthermore, KIM-1, TIMP-1, IL-33, and MMP-2 were downregulated by spexin treatment. Renal damage, NGAL, TIMP-1 IL-17A, IL-33, MMP-2, and MMP-3 decreased after adropin treatment, while MMP-13 levels were upregulated. Treatment with adropin+spexin decreased KIM-1, NGAL, TIMP-1, IL-1β, IL-17A, IL-18, IL-33, ALOX 15, COX 1, COX 2, TGFβ1, TNFα, MMP-2, MMP-3, and MMP-7, but increased MMP-13 levels. Our findings revealed that inflammatory response and MMP genes were modulated by adropin and spexin. These peptides may have protective effects on inflammation and chronic kidney damage progression.

Keywords: Chronic kidney failure; adropin; inflammation; matrix metalloproteinase; spexin.

Figure 1.

Effects of adropin and spexin on macroscopic appearance, histopathologic changes, and tubular necrosis in a model of adenine-induced CKF. Renal histopathological changes and tubular necrosis were examined by H&E staining. The red arrow indicates a glomerular area and the blue arrow indicates tubular necrosis. Photographs taken at 200× magnification (scale bar = 50 μm). Data are expressed as mean ± S.D. One-way ANOVA, Mann–Whitney U test. ^****p < 0.0001 vs. vehicle group. ⁺⁺P < 0.01 vs. CKF group (n= 5). (A color version of this figure is available in the online journal.)

Figure 2.

Effects of adropin and spexin on markers of kidney damage in CKF. mRNA expression levels of KIM-1, NGAL, and TIMP-1 in kidney tissue were measured by qRT-PCR and normalized to β-actin. Data are expressed as mean ± S.D. One-way ANOVA, Mann–Whitney U test. ^**p < 0.01 vs. vehicle group. ⁺⁺p < 0.01 and ⁺p < 0.05 vs. CKF group (n= 5).

Figure 3.

Effects of adropin and spexin on the expression of interleukin genes in CKF. mRNA expression levels of IL-1β, IL-10, IL-17A, IL-18, IL-21, and IL-33 in kidney tissue were measured by qRT-PCR and normalized to β-actin. Data are expressed as mean ± S.D. One-way ANOVA, Mann–Whitney U test. ^**p < 0.01 vs. vehicle group. ⁺⁺⁺p < 0.001, ⁺⁺p < 0.01, and ⁺p < 0.05 vs. CKF group (n= 5).

Figure 4.

Adropin and spexin alter proinflammatory and anti-inflammatory genes in CKF. mRNA expression levels of ALOX15, COX-1, COX-2, TGF-β1, and TNF-α in kidney tissue were measured by qRT-PCR and normalized to β-actin. Data are expressed as mean ± S.D. One-way ANOVA, Mann–Whitney U test. ^*p < 0.05 vs. vehicle group. ⁺⁺⁺p < 0.001, ⁺⁺p < 0.01, and ⁺p < 0.05 vs. CKF group. ^¥¥p < 0.01 and ^¥p < 0.05 vs. adropin (n= 5).

Figure 5.

Adropin and spexin regulate MMP genes in CKF. mRNA expression levels of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, and MMP-13 in kidney tissue were measured by qRT-PCR and normalized to β-actin. Data are expressed as mean ± S.D. One-way ANOVA, Mann–Whitney U test. ^**p < 0.01 vs. vehicle group. ⁺⁺⁺p < 0.001, ⁺⁺p < 0.01, and ⁺p < 0.05 vs. CKF group. ^¥p < 0.05 vs. adropin (n= 5).