Perizyten MDM2-β8 Integrin Signalisierung in der Pathogenese der diabetischen Nephropathie und Retinopathie
Zusammenfassung der Projektergebnisse
In this project we successfully constructed pericyte specific mouse double minute 2 homolog knockout (MDM2-KO) mice. MDM2-KO increased integrin β8 (ITGB8) expression. MDM2-KO prevented the vascular damage in diabetes by reducing acellular capillary formation and pericyte loss with inhibited glial activation and cellular apoptosis in the retinas. More importantly, MDM2-KO attenuated hyperglycemiainduced retinal damages, especially the fibrosis injury, due to reduced deposition of extracellular matrix protein. Moreover, MDM2-KO reversed the diabetes-induced axis activation of MDM2-ITGB8-transforming growth factor beta 1 (TGF-β1) pathway, induced by diabetes. In vitro experiments confirmed that high glucose (HG)-induced MDM2 upregulation inhibited ITGB8 expression in pericytes, and promoted mothers against decapentaplegic homolog 3 (SMAD3) phosphorylation and translocation. On the contrary MDM2-knockdown recovered ITGB8 expression and reduced activation of TGF-β downstream signaling. As a consequence of inactivated MDM2-ITGB8-TGF- β1 axis, the deposition of fibrosis-related proteins were attenuated. Therefore, conditional pericyte MDM2-KO prevents the development of diabetic retinopathy (DR). In the kidney, hyperglycemia-induced MDM2 expression led to the reduction of ITGB8 and activation of TGF-β1 downstream signaling, along with upregulation of fibronectin and alpha smooth muscle actin (α-SMA). MDM2-KO mitigated glomerular sclerosis and renal fibrosis and significantly improved diabetic renal function with the amelioration of blood urea nitrogen (BUN) and urine albumin-creatinine ratio (uACR). In short-term (three months) diabetes, renal EMT is present and can be reduced by MDM-KO, whereas in long-term (six months) diabetes, the EMT is of minor relevance. Renal fibrosis injury was the main manifestation due to activation of the MDM2-ITGB- TGF-β1 signaling axis. MDM2-KO avoided renal fibrosis and maintained the expression of cadherins. Conversely, ITGB8 overexpression lessened renal fibrosis damage and ameliorated renal function. Therefore, MDM2-ITGB8-TGFβ1 axis is important in retinal and renal fibrosis. Targeting MDM2 may be a novel therapeutic strategy for the treatment of disease of fibrosis.
Projektbezogene Publikationen (Auswahl)
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Regulation of Podocyte Injury by CircHIPK3/FUS Complex in Diabetic Kidney Disease. International Journal of Biological Sciences, 18(15), 5624-5640.
Liu, Feng; Huang, Jing; Zhang, Chunyun; Xie, Yaru; Cao, Yiling; Tao, Li; Tang, Hui; Lin, Jihong; Hammes, Hans-Peter; Huang, Kun; Yi, Fan; Su, Hua & Zhang, Chun
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MDM2 knockout prevents mouse diabetic retinopathy, 33rd EAsDEC Conference (2023), Coimbra, Portugal
Chen Y.; Jin F.; Li L.; Kurowski, L. & Hammes HP, Lin J.
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miRNA-124 Prevents Rat Diabetic Retinopathy by Inhibiting the Microglial Inflammatory Response. International Journal of Molecular Sciences, 24(3), 2291.
Chen, Ying; Schlotterer, Andrea; Kurowski, Luke; Li, Lin; Dannehl, Marcus; Hammes, Hans-Peter & Lin, Jihong
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Integrin β8 prevents pericyte-myofibroblast transition and renal fibrosis through inhibiting the TGF-β1/TGFBR1/Smad3 pathway in diabetic kidney disease. Translational Research, 265, 36-50.
Cao, Yiling; Su, Hua; Zeng, Jieyu; Xie, Yaru; Liu, Zezhou; Liu, Feng; Qiu, Yang; Yi, Fan; Lin, Jihong; Hammes, Hans-Peter & Zhang, Chun
