COMMD5 counteracts drug-induced acute nephrotoxicity and chronic renal fibrosis by maintaining tubular epithelial barrier.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08239
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Nihon University
• Principal Investigator: MATSUDA Hiroyuki 日本大学, 医学部, 助教 (10646037)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: COMMD5 / HCaRG / 急性腎障害 / 慢性腎臓病 / 尿細管上皮バリア / 尿細管上皮の完全性 / E-cadherin / オートファジー

Outline of Final Research Achievements

COMMD5/HCaRG is highly expressed in renal proximal tubules (PTs), where it controls cell differentiation. We assessed its role in cisplatin-induced acute kidney injury and chronic kidney disease progression using transgenic mice in which COMMD5 is overexpressed in the PTs. Cisplatin caused the accumulation of damaged mitochondria and cellular waste in PTs, thus increasing the apoptosis. COMMD5 effectively protected PTs from cisplatin nephrotoxicity, thus alleviating acute renal dysfunction and chronic renal fibrosis. Mechanistically, excessive damages by drug treatment led to impaired autophagy flux through an increased burden on the autophagy/lysosome degradation system in PTs, and autophagic elimination of damaged mitochondria and cellular waste was compromised. COMMD5 reduced mitochondrial dysfunction and increased autophagy flux by alleviating damages through maintaining tubular epithelial barrier. Increasing COMMD5 is proposed as a new protective strategy against kidney diseases.

Free Research Field

腎臓内科学

Academic Significance and Societal Importance of the Research Achievements

上皮細胞は、生体内の内部環境と外部環境を隔て、生体の恒常性を維持する役割を担っている。本研究では、COMMD5/HCaRGが、細胞内膜タンパク輸送体を形成し、尿細管上皮細胞の完全性維持に必要な細胞間構造の構成タンパク質などの発現を調整し、腎障害の発症と進展を抑制していることが示唆された。現在、日本の血液透析患者数は、2017年に33万人を超えて増加の一途をたどっており、年間1兆6000億円に上ると推計される医療費も社会的問題となっている。今後、COMMD5を標的とした新たな腎臓病の治療法や予防法へと応用でき、透析導入患者を減らし、医療費の削減へ繋がると期待される。