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Renoprotection of Microcystin-RR in Unilateral Ureteral Obstruction-Induced Renal Fibrosis: Targeting the PKM2-HIF-1α Pathway.

ABSTRACT: Renal fibrosis is a pathological characteristic of the endpoint of chronic kidney disease (CKD), which remains a major public health problem. None of the current therapies is effective in stopping kidney fibrosis progression. In light of our novel detection of a potential antifibrosis of microcystins (MCs), we investigate the renoprotection effect of MCs with UUO-induced renal fibrosis. The treatment of MCs was initiated in model animals in advance of UUO operation. After determining that the antifibrotic effect of MCs was independent of its toxicity, our study focused on the renoprotection of microcystin-RR (MC-RR), a lower toxic congener of MCs, in UUO mice and the cell models in vitro. The co-immunoprecipitation assay and recombination plasmid transfection were used in the investigation of the mechanism of antifibrosis of MC-RR. The data show that MC-RR substantially exerts an effect on renoprotection with suppression of the expression of TGF-β1/Smad signaling molecules and a blockage in epithelial dedifferentiation and myofibroblast activation in UUO model animals. MC-RR shows a binding directly to pyruvate kinase M2 (PKM2), downregulates PKM2-HIF-1α signaling, restores the inhibited expression of MMP-7 and MMP-13, and reduces the upregulated expression of MMP-9 in UUO renal tissues. The current study demonstrates a novel effect of MC-RR on renoprotection in kidney damage, which could be conducted in therapeutics for chronic kidney disease.

SUBMITTER: Ren Y

PROVIDER: S-EPMC9218570 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Although the primary organ has been the subject of intense investigation in the field of organ fibrosis over the past several decades, the presence of lymph node fibrosis due to persistent activation of the immune response in its partner organ remains largely unknown. Previously, we demonstrated that activation of the immune response following ischemia-reperfusion injury (IRI) and crescentic glomerulonephritis (CGN) in the kidney was associated with extracellular matrix (ECM) production by fibroblastic reticular cells (FRCs) of the kidney-draining lymph node (KLN). Here, we sought to determine whether FRCs in the KLN become similarly fibrogenic following unilateral ureteral obstruction (UUO) of the kidney. We subjected 6-8-week-old C57BL/6J mice to UUO for 2, 7, and 14 days. We examined the microarchitecture of the kidney and KLN by immunofluorescence staining at each timepoint, and we quantified immune cell populations in the KLN by flow cytometry. The contralateral kidney unaffected by UUO and its partner KLN were used as controls. We found through immunofluorescence staining that FRCs increased production of ECM fibers and remodeled the microarchitecture of the UUO KLN, contributing to fibrosis that mirrored the changes in the kidney. We also observed by flow cytometry that the populations of CD11b+ antigen-presenting cells, CD11c+ dendritic cells, and activated CD4+ and CD8+ T cells were significantly higher in the UUO KLN than the KLN draining the unaffected contralateral kidney. Expression of the TGFβ/TGFβR signaling pathway was upregulated and colocalized with FRCs in the UUO KLNs, suggesting a possible mechanism behind the fibrosis. Both release of ureteral ligation at 2 days following UUO and depletion of FRCs at the time of injury onset halted the progression of fibrosis in both the kidney and the KLN. These findings for the first time highlight the association between fibrosis both in the kidney and the KLN during UUO, and they lay the groundwork for future studies that will investigate more deeply the mechanisms behind the connection between FRCs and KLN fibrosis.

Dataset Information

Renoprotection of Microcystin-RR in Unilateral Ureteral Obstruction-Induced Renal Fibrosis: Targeting the PKM2-HIF-1α Pathway.

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