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LTBP4 affects renal fibrosis by influencing angiogenesis and altering mitochondrial structure.

ABSTRACT: Transforming growth factor beta (TGFβ) signalling regulates extracellular matrix accumulation known to be essential for the pathogenesis of renal fibrosis; latent transforming growth factor beta binding protein 4 (LTBP4) is an important regulator of TGFβ activity. To date, the regulation of LTBP4 in renal fibrosis remains unknown. Herein, we report that LTBP4 is upregulated in patients with chronic kidney disease and fibrotic mice kidneys created by unilateral ureteral obstruction (UUO). Mice lacking the short LTBP4 isoform (Ltbp4S^-/-) exhibited aggravated tubular interstitial fibrosis (TIF) after UUO, indicating that LTBP4 potentially protects against TIF. Transcriptomic analysis of human proximal tubule cells overexpressing LTBP4 revealed that LTBP4 influences angiogenic pathways; moreover, these cells preserved better mitochondrial respiratory functions and expressed higher vascular endothelial growth factor A (VEGFA) compared to wild-type cells under hypoxia. Results of the tube formation assay revealed that additional LTBP4 in human umbilical vein endothelial cell supernatant stimulates angiogenesis with upregulated vascular endothelial growth factor receptors (VEGFRs). In vivo, aberrant angiogenesis, abnormal mitochondrial morphology and enhanced oxidative stress were observed in Ltbp4S^-/- mice after UUO. These results reveal novel molecular functions of LTBP4 stimulating angiogenesis and potentially impacting mitochondrial structure and function. Collectively, our findings indicate that LTBP4 protects against disease progression and may be of therapeutic use in renal fibrosis.

SUBMITTER: Su CT

PROVIDER: S-EPMC8514500 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHeat stress in laying hens negatively affects egg production and shell quality by disrupting the homeostasis of plasma calcium and phosphorus levels. Although the kidney plays an important role in calcium and phosphorus homeostasis, evidence regarding the effect of heat stress on renal injury in laying hens is yet to be elucidated. Therefore, the aim of this study was to evaluate the effects of chronic heat stress on renal damage in hens during laying periods.MethodsA total of 16 white-leghorn laying hens (32 weeks old) were randomly assigned to two groups (n = 8). One group was exposed to chronic heat stress (33 °C for 4 weeks), whereas the other group was maintained at 24 °C.ResultsChronic heat exposure significantly increased plasma creatinine and decreased plasma albumin levels (P < 0.05). Heat exposure also increased renal fibrosis and the transcription levels of fibrosis-related genes (COLA1A1, αSMA, and TGF-β) in the kidney. These results suggest that renal failure and fibrosis were induced by chronic heat exposure in laying hens. In addition, chronic heat exposure decreased ATP levels and mitochondrial DNA copy number (mtDNA-CN) in renal tissue, suggesting that renal mitochondrial dysfunction occurs under conditions of heat stress. Damaged mitochondria leak mtDNAs into the cytosol and mtDNA leakage may activate the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) signaling pathway. Our results showed that chronic heat exposure activated the cGAS-STING pathway as indicated by increased expression of MDA5, STING, IRF7, MAVS, and NF-κB levels. Furthermore, the expression of pro-inflammatory cytokines (IL-12) and chemokines (CCL4 and CCL20) was upregulated in heat-stressed hens.ConclusionsThese results suggest that chronic heat exposure induces renal fibrosis and mitochondrial damage in laying hens. Mitochondrial damage by heat stress may activate the mtDNA-cGAS-STING signaling and cause subsequent inflammation, which contributes to the progression of renal fibrosis and dysfunction.

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LTBP4 affects renal fibrosis by influencing angiogenesis and altering mitochondrial structure.

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