The purpose of this research

In this research program, we try to study the detailed development mechanisms of Fanconi syndrome (FS) and Bartter syndrom (BS), and their preventation.

What are Fanconi syndrome (FS) and Bartter syndrome (BS)?

The human kidney is composed of a million of its functional units, nephrons. A single nephron consists of a renal corpuscle attached to a renal tubule. The proximal tubule, which immediately follows the renal corpuscle is one of the most important segments in the nephron, and is involved in reabsorption of vital molecules such as glucose and amino acids as well as electrolytes and water. Fanconi syndrome (FS) is the general functional disorder of proximal tubules, and is a syndrome in which many substances cannot be reabsorbed and wasted in urine. The loop of Henle is the characteristic structure that leads from the proximal tubule to the distal tubule. Extensive electrolyte reabsorption is carried out in the thick ascending limb of the loop of Henle (TAL). Bartter syndrome (BS) is a functional transport disorder of the TAL, and is a syndrome characterized by hypotension, hypokalemia and metabolic alkalosis.

p1_01

In the physiological conditions, blood is filtered at the glomeruli. Essential components in the filtrate are re-absorbed whereas unnecessary components are excreted in the urine.

y2 More detail

Symptom

The process of bone mineralization is impaired due to the defect of phosphate reabsorption and activation of vitamin D. Consequently, rickets is observed in child patients whereas osteomalacia is observed in adult patients. Growth retardation is observed in patients due to the impairment of reabsorption of nutrients such as glucose and amino acids, which are important for energy metabolism and growth. Metabolic acidosis, abnormality of electrolytes, and dehydration are also observed in patients.

Etiology

FS is both congenital and acquired and caused by a variety of factors. The congenital FS includes Dent disease and Lowe syndrome. CLCN5 (a gene encoding a chloride channel) and OCRL1 (a gene encoding phosphatase) are causative genes for Dent disease and Lowe syndrome, respectively. Many other genes were identified as causative genes for FS. FS is also caused by heavy metals (cadmium and platinum) and drugs (anti-cancer agents, antibiotics, and aristolochic acid).

Prevention/Treatment

The treatment for FS is different depending on the cause of the disease. If left untreated, it may lead to the chronic kidney disease. In the case of acquired FS, patient should refrain from using the drug and be replenished with electrolytes which was lost from the tubules such as phosphate and K+ as symptomatic treatment

p1_close

Subjects of this research

p1_i2

FS is a broad range of dysfunction of renal proximal tubules caused by a variety of factors.It may be caused not only by congenital factors but also by acquired factors such as drug administration. Therefore, the molecular mechanisms leading to the development seem to be variable.

In this research program, we try to clarify the step-by step changes in tissues and organisms in the process of FS to kidney failure using the FS model mice and cell lines derived from kidney proximal tubules by biochemical, histological, and electrophysiological techniques. We also try to study the methods of FS prevention and treatment.

We try to prepare the drug-induced FS model mice and clarify the expression mechanism of toxicity which is specific for renal proximal tubules.

FS is a broad range of dysfunction of renal proximal tubules. We try to study the expression of transporters, and the related scaffold proteins and cytoskeletal proteins by using the FS model mice and cultured cells. We also try to clarify the behavior of FS gene product in the cells.

We try to search candidate compounds which show the effect of prevention and treatment on FS by using these FS models.

transporter(A, B, C)

Many transporters (A, B, and C) on the plasma membrane are associated with the same platform of scaffold protein containing multiple PDZ domains (NHERF). The scaffold protein is fixed on the cytoskeleton through an actin-binding protein, ezrin. Therefore, the missing of the scaffold and adaptor proteins results in the functional defects of multiple transporters, which are found in FS.

Project members

浅野 真司

Shinji AsanoProfessor, College of Pharmaceutical Sciences, Department of Pharmacy

藤田 典久

Norihisa FujitaEmeritus Professor, College of Pharmaceutical Sciences, Department of Pharmacy

川口 高徳

Kotoku KawaguchiAssistant Professor, College of Pharmaceutical Sciences, Department of Pharmacy

Other Research subjects

Functional analysis of causative genes for Rett syndrome

Rett syndrome (RTT) is a rare disease that is associated with mental retardation, epilepsy, autism, stereotyped movements of the hands. RTT affects 1 in 10,000~15,000 girls worldwide, and it is reported that an estimated 5,000 patients exist in Japan.
In this research, we aim to propose therapeutic options by clarifying the mechanism of the onset of Rett syndrome.

y2 For more information

Functional analysis of the gene products related to Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by loss of expression of paternal genes on chromosome 15. Major characteristics includes short stature, obesity, hypogonadism, respiratory distress, pain insensitivity and cognitive delays.
We will focus on the features of PWS that are related to obesity in order to understand the mechanisms involved in its pathogenesis and to explore novel therapeutic options.

y2 For more information

Elucidation of the mechanism underlying laminopathies and development of their therapies

The goals of our research are to elucidate the mechanism underlying two laminopathies and to develop new therapies for these diseases by cutting-edge methods of various research fields including proteomics, cell biology, in silico structural biology, and drug design.

y2 For more information