Pericyte MDM2-β8 integrin signaling in the pathogenesis of diabetic nephropathy and retinopathy

• Applicant: Dr. Jihong Lin
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431381214

Diabetic nephropathy (DN) and diabetic retinopathy (DR) are the major microvascular complications. Pericyte impairment is the earliest and most important cellular event in DN (mesangial cells) and DR. Pericytes are essential for the regulation of angiogenesis, vascular architecture and permeability. Renal pericytes are particularly sensitive to high glucose, leading to the pathology of DN. Peritubular pericytes are considered as the same population of fibroblasts and their transition to myofibroblasts is a cardinal event during interstitial fibrosis. Glomerular pericytes (mesangial cells) undergo proliferation and expansion, which are morphological characteristics of DN. Likewise, DR is characterized by pericyte loss which can cause vasoregression. Better understanding of the mechanisms of integrin signaling in pericyte injury during DN and DR is fundamental to improve therapeutic concepts.MDM2 is an E3 ubiquitin ligases. Besides classic p53 ubiquitination and degradation, MDM2 also exerts p53-independent functions. Overexpression of MDM2 promotes peritubular pericyte-to-myofibroblast activation and collagen deposition in obstructive nephropathy, and participates in mesangial cell proliferation and expansion in DN. Unexpectedly, interrupting the MDM2-p53 pathway cannot attenuate these disturbances. In the retina, MDM2 regulates the pericyte population in laser-induced vasculopathy. However, whether it is implicated in pericyte impairment and DR remains unclear.Integrins consist of α and β subunits. The β subunit serves as cytoskeleton binding site for signal transduction, while the α subunit serves as a regulator. Interestingly, β8 is an exception without cytoskeleton binding sites, but it distinctively controls TGF-β1 activity. β8 only interacts with αv which is involved in DR and DN. Although targeting αv is curative for diabetes, the role of the β subunit, especially in β8-TGF-β1 signaling, is unclear. Integrin β8 is expressed prominently in the kidney. Retinal astrocyte-derived β8 is critical for development of retinal vessels. In glomeruli, β8 is selectively localized to mesangial cells with an obvious reduction in sclerotic mesangial region. Our preliminary data indicate that β8 is ubiquitinated and degraded with enhanced binding to MDM2, which can be ameliorated by MDM2 deletion both in fibroblasts and mesangial cells. In the retinae from cornea donors, integrin β8 mRNA was detected but its function was unknown. Hence, we hypothesize that overexpression of MDM2 in pericytes potentiates integrin β8 ubiquitination and degradation and ultimately results in TGF-β1 activation in the pathogenesis of DN and DR. To verify this hypothesis we use conditional pericyte MDM2-KO and integrin β8 transgenic mice to evaluate the role of MDM2-integrin β8-TGF-β1 signaling in diabetes. This investigation will shed light on the pathogenesis of DN and DR and provide strategies for diabetic microvascular complications.

• DFG Programme: Research Grants
• International Connection: China
• Partner Organisation: National Natural Science Foundation of China
• Cooperation Partners: Professorin Hua Su; Dr. Yumei Wang; Professor Chun Zhang, Ph.D.
• Co-Investigator: Professor Dr. Hans-Peter Hammes