Role of local inflammation in the kidney for the development and progression of chronic kidney disease and its regulation toward novel therapeutic strategy

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09706
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kumamoto University
• Principal Investigator: MUKOYAMA Masashi 熊本大学, 大学院生命科学研究部(医), 教授 (40270558)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 慢性腎臓病 / 糖尿病性腎症 / 腎炎 / 自然炎症 / マクロファージ / ERストレス / ANGPTL2 / MRP8

Outline of Final Research Achievements

Diabetes and glomerulonephritis are the leading cause of chronic kidney disease (CKD), an important disease category with high prevalence in Japan. The mechanisms for CKD development and progression are still poorly understood, and therefore we investigated the role of chronic homeostatic inflammation in the kidney in this pathophysiology.
We found that a macrophage-derived proinflammatory factor MRP8 (myeloid-related protein 8, or S100A8) is critical in the progression of nephrotoxic serum-induced glomerulonephritis in mice, by affecting macrophage characterization toward an M1 phenotype. In human studies, the serum MRP8/MRP14 heterodimer level was increased in chronic hemodialysis patients, which was significantly associated with high risk of all-cause mortality among the high phosphate group. Also, a high serum level of ANGPTL2 was an independent risk factor for all-cause mortality in hemodialysis patients. These findings may provide potential therapeutic targets for CKD.

Free Research Field

内科系臨床医学・腎臓内科学

Academic Significance and Societal Importance of the Research Achievements

生活習慣病や腎炎における局所因子の意義、特にマクロファージ由来MRP8の増悪因子としての役割を明らかにすることで、これをターゲットとした新たな創薬への基盤となる。さらに、急性腎障害の慢性化に及ぼす因子を明らかにすることにより、それらへの介入によって腎症進展抑止のための治療戦略となる。MRP8やANGPTL2はその候補分子であり、これらを標的とした治療法はなく、病態での意義の解析から新たな治療戦略の提案へとつながる可能性がある。一方で、これらの血中濃度高値は透析患者の予後と相関することから、バイオマーカーとしての意義が示唆され、今後の腎疾患診療に対して多大な波及効果をもたらすと考えられる。