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Peptide E from Bifidobacterium adolescentis LA20-k9 fermentation inhibits feline renal cellular senescence via the SMAD7/p-SMAD3/IL6-CXCL8 axis

ABSTRACT: Aging is an inevitable biological phenomenon that drives progressive functional decline at cellular and tissue levels, with chronic kidney disease (CKD) affecting up to 80% of cats over 15 years of age. Probiotic-derived metabolites hold anti-aging promise, but their renal protective mechanisms remain largely undefined. In this study, we investigated the anti-senescence effects of fermented brown algae extracts from Bifidobacterium adolescentis LA20-K9 (LA20FM) on feline kidney cells. Both the LA20FM<3 kDa and LA20FM>30 kDa molecular weight fractions mitigated doxorubicin-induced senescence, as evidenced by reduced SA-β-gal activity and decreased CDKN1A/CDKN2A expression. Peptide E, which was isolated from the LA20FM<3 kDa fraction, was identified as the principal bioactive component. RNA-sequencing revealed that peptide E downregulated senescence-associated genes, including IL6, CXCL8, GDF15, and KRT15, while upregulating the anti-senescence gene SMAD7. Mechanistically, peptide E enhanced SMAD7 expression, which in turn suppressed SMAD3 phosphorylation and consequently reduced IL6 and CXCL8 transcription. Crucially, SMAD7 knockdown completely abrogated these protective effects. Collectively, our findings identify peptide E as a novel bioactive peptide that antagonizes renal cellular senescence via the SMAD7/p-SMAD3/IL6-CXCL8 axis, offering a potential therapeutic candidate for age-related kidney dysfunction in felines.

ORGANISM(S): Felis catus

PROVIDER: GSE337653 | GEO | 2026/07/07

REPOSITORIES: GEO

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Project description:Rationale: Expansion and activation of cardiac fibroblasts contributes to adverse remodeling, fibrosis and dysfunction in the pressure-overloaded heart. Although early fibroblast TGF-β/Smad3 activation protects the pressure overloaded heart by preserving the matrix, sustained TGF-β activation may be deleterious, accentuating fibrosis and dysfunction. Thus, endogenous mechanisms that negatively regulate the TGF- response in fibroblasts may be required to protect from progressive fibrosis and adverse remodeling. Objective: To study the role of fibroblast-specific induction of Smad7, an inhibitory Smad that restrains TGF-β signaling, in regulation of fibrosis, remodeling and dysfunction of the pressure-overloaded heart. Methods and Results: In a mouse model of pressure overload induced through transverse aortic constriction (TAC), Smad7 was upregulated in cardiac myofibroblasts. Mice with myofibroblast-specific loss of Smad7 (MFS7KO) had increased mortality, accentuated systolic dysfunction and dilative remodeling, and accelerated diastolic dysfunction in response to TAC. Increased dysfunction in MFS7KO hearts was associated with accentuated fibrosis and increased collagen denaturation, in the absence of effects on cardiomyocyte death. Secretomic analysis showed that Smad7 loss accentuates secretion of structural collagens and matricellular proteins, and markedly increases secretion of matrix metalloproteinase-2 (MMP2). In a 3D model of fibroblasts populating collagen lattices the effects of Smad7 on fibroblast-induced collagen denaturation and pad contraction were partly mediated via MMP2 downregulation. Surprisingly, MFS7KO mice also exhibited significant macrophage expansion caused by paracrine actions of Smad7 null fibroblasts that stimulate macrophage proliferation and fibrogenic activation. Secretomic analysis and in vitro experiments suggested that macrophage activation involves the combined effects of the fibroblast-derived matricellular proteins CD5L, SPARC, CTGF, ECM1 and TGFBI. Conclusions: The anti-fibrotic effects of Smad7 in the pressure-overloaded heart protect from dysfunction and involve not only reduction in collagen deposition, but also suppression of MMP2-mediated matrix denaturation and paracrine effects that suppress macrophage activation through inhibition of matricellular proteins.

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Peptide E from Bifidobacterium adolescentis LA20-k9 fermentation inhibits feline renal cellular senescence via the SMAD7/p-SMAD3/IL6-CXCL8 axis

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