武内 恒成

Patients undergoing long-term peritoneal dialysis (PD) frequently develop peritoneal fibrosis and angiogenesis, leading to membrane dysfunction. Transglutaminase 2 (TG2) stabilizes the extracellular matrix against proteases. In an animal model, inhibition of TG2 reduced peritoneal fibrosis, angiogenesis, and inflammation. We investigated the expression of TG2 in 163 human peritoneal membrane tissue samples, including controls, tissues exposed to conventional acidic or low-glucose degradation product (GDP) pH-neutral solutions, and those with peritonitis or encapsulating peritoneal sclerosis (EPS), and explored the role of TG2 in high-glucose-induced pathophysiology in mesothelial cells. TG2 expression was upregulated in association with peritoneal membrane injury and was the highest in peritonitis. TG2 expression was correlated with peritoneal membrane thickness, CD68-positive macrophages, and myofibroblast expression. TG2 was expressed in mesothelial cells, α-smooth muscle actin-positive myofibroblast expression, macrophages, and endothelial cells in the diseased state. In cultured mesothelial cells, high-glucose-induced upregulation of collagen 1, TGF-β1, and TG2 was suppressed by a TG2 inhibitor or by TGF-β1 small interfering RNA. TG2 is involved in the development of peritoneal injury during PD. High-glucose dialysate is involved in the induction of peritoneal fibrosis through the interactive regulation of TGF-β and TG2. Targeting TG2 may offer therapeutic potential for managing PD complications and EPS.

AIM: Renal fibrosis is a final common pathway for progressive chronic kidney diseases. Immune cell infiltration and production of tumour growth factor-β (TGF-β) are essential factors for fibrosis development. We examined the role of chondroitin sulfate (CS) proteoglycan, which is one of the main extracellular matrix components induced by TGF-β signalling. We also examined CS N-acetylgalactosaminyltransferase 1 (T1), an enzyme that catalyses the first step of CS-specific synthesis. METHODS: T1-/- mice, genetically lacking T1, and T1+/+ mice underwent 5/6 nephrectomy (Nx) or sham operation. Kidney function, urine marker, mRNA expression, and TGF-β signalling were evaluated 1 month after Nx or sham operation. Renal fibrotic area was quantified 3 months later. RESULTS: Both T1+/+ and T1-/- mice with Nx showed equivalent loss of kidney function; however, a tubular damage marker, upregulation of TGF-β and collagen expression, and renal fibrosis were suppressed in T1-/- mice with Nx. Versican, one of the core proteins of CS proteoglycan, was exclusively upregulated in T1+/+ mice with Nx. Among the versican splicing variants, versican 1 (V1) was expressed in the medullary interstitium of the remnant kidney in T1+/+ mice. V1 was produced in the interstitial macrophages, fibroblasts/myofibroblasts, and endothelial cells, whereas TGF-β was expressed in fibroblasts/myofibroblasts. Phosphorylation of the TGF-β signalling molecules Smad2/3 was not induced in T1-/- mice with Nx. In vivo administration of TGF-β inhibitor into Nx mice reduced V1 and Tgfb expression. CONCLUSION: T1 was essential for effective TGF-β signalling, V1 upregulation, and subsequent renal fibrosis.

Chondroitin extends lifespan and healthspan in C. elegans, but the relationship between extracellular chondroitin and intracellular anti-aging mechanisms is unknown. The basement membrane (BM) that contains chondroitin proteoglycans is anchored to cells via hemidesmosomes (HDs), and it accumulates damage with aging. In this study, we found that chondroitin regulates aging through the formation of HDs and inhibition of tubular lysosomes (TLs). Reduction of chondroitin due to a mutation in sqv-5/Chondroitin synthase (ChSy) causes the earlier and excessive formation of TLs and leakage of the lysosomal nuclease in a manner dependent on VHA-7, the a-subunit of V-type ATPase. VHA-7, whose mutation suppresses the short lifespan of the sqv-5 mutant, is initially localized to the basal side of the hypodermal cells and transported to lysosomes with aging. These results demonstrate that endogenous chondroitin suppresses aging by inhibiting the earlier excessive formation of TLs. This is a novel anti-aging mechanism that is controlled by the BM.

Chondroitin, a class of glycosaminoglycan polysaccharides, is found as proteoglycans in the extracellular matrix, plays a crucial role in tissue morphogenesis during development and axonal regeneration. Ingestion of chondroitin prolongs the lifespan of C. elegans. However, the roles of endogenous chondroitin in regulating lifespan and healthspan mostly remain to be investigated. Here, we demonstrate that a gain-of-function mutation in MIG-22, the chondroitin polymerizing factor (ChPF), results in elevated chondroitin levels and a significant extension of both the lifespan and healthspan in C. elegans. Importantly, the remarkable longevity observed in mig-22(gf) mutants is dependent on SQV-5/chondroitin synthase (ChSy), highlighting the pivotal role of chondroitin in controlling both lifespan and healthspan. Additionally, the mig-22(gf) mutation effectively suppresses the reduced healthspan associated with the loss of MIG-17/ADAMTS metalloprotease, a crucial for factor in basement membrane (BM) remodeling. Our findings suggest that chondroitin functions in the control of healthspan downstream of MIG-17, while regulating lifespan through a pathway independent of MIG-17.