Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome

Alport syndrome (AS) is a progressive inherited kidney disease characterized by hearing loss and ocular abnormalities.There are three forms of AS depending on inheritance mode: X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, which encodes type IV collagen α5 chain, while ADAS and ARAS are caused by variants in COL4A3 or COL4A4, which encode type IV collagen α3 or α4 chain, respectively. In male XLAS or ARAS cases, end-stage kidney disease (ESKD) develops around a median age of 20 to 30 years old, while female XLAS or ADAS cases develop ESKD around a median age of 60 to 70 years old. The diagnosis of AS is dependent on either genetic or pathological findings. However, determining the pathogenicity of the variants detected by gene tests can be difficult. Recently, we applied the following molecular investigation tools to determine pathogenicity: 1) in silico and in vitro trimer formation assay of α345 chains to assess triple helix formation ability, 2) kidney organoids constructed from patients’ induced pluripotent stem cells to identify α5 chain expression on the glomerular basement membrane, and 3) in vitro splicing assay to detect aberrant splicing to determine the pathogenicity of variants. In this review article, we discuss the genetic background and novel assays for determining the pathogenicity of variants. We also discuss the current treatment approaches and introduce exon skipping therapy as one potential treatment option.

Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome

Alport syndrome (AS) is a progressive inherited kidney disease characterized by hearing loss and ocular abnormalities.There are three forms of AS depending on inheritance mode: X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, which encodes type IV collagen α5 chain, while ADAS and ARAS are caused by variants in COL4A3 or COL4A4, which encode type IV collagen α3 or α4 chain, respectively. In male XLAS or ARAS cases, end-stage kidney disease (ESKD) develops around a median age of 20 to 30 years old, while female XLAS or ADAS cases develop ESKD around a median age of 60 to 70 years old. The diagnosis of AS is dependent on either genetic or pathological findings. However, determining the pathogenicity of the variants detected by gene tests can be difficult. Recently, we applied the following molecular investigation tools to determine pathogenicity: 1) in silico and in vitro trimer formation assay of α345 chains to assess triple helix formation ability, 2) kidney organoids constructed from patients’ induced pluripotent stem cells to identify α5 chain expression on the glomerular basement membrane, and 3) in vitro splicing assay to detect aberrant splicing to determine the pathogenicity of variants. In this review article, we discuss the genetic background and novel assays for determining the pathogenicity of variants. We also discuss the current treatment approaches and introduce exon skipping therapy as one potential treatment option.

The Role of Heat Shock Response in Insulin Resistance and Diabetes

The expansion of life-style related diseases, such as metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM), appears to be unstoppable. It is also difficult to cease their complications in spite of many antidiabetic medications or intervention of public administration. We and our collaborators found that physical medicine using simultaneous stimulation of heat with mild electric current activates heat shock response, thereby reducing visceral adiposity, insulin resistance, chronic inflammation and improving glucose homeostasis in mice models of T2DM, as well as in humans with MS or T2DM. This combination therapy exerts novel action on insulin signaling, beta-cell protection and body compositions, and may provide a new therapeutic alternative in diabetic treatment strategy.

Glucocorticoid-like and Glucocorticoid-unlike Regulation of Gene Expression by Bakumondo-to(Mai-Men-Dong-Tang) in Airway Epithelial Cells / 日本東洋医学雑誌

Since many patients are still dying from asthma and COPD, developing more effective drugs with little side-effect which can be taken for a long time, is very important. Clinical usage of herbal medicines for chronic airway diseases has been increasing. Bakumondo-to is a useful herbal medicine with little side-effect for the treatment of chronic airway diseases. There are some similarities of pharmacological profile of herbal medicines to those of glucocorticoids. Although the regulation of gene expression by glucocorticoids has been clarified, that of Bakumondo-to is not well known. Elucidation of the mechanism of Bakumondo-to will be helpful in establishing a more effective treatment of chronic airway diseases. This article focuses on the regulation of gene expression by Bakumondo-to in airway epithelial cells, and describes the increase in mRNA expression for β-adrenergic receptors by Bakumondo-to and in glucocorticoid-sensitive promoter activity. We also discuss the mechanisms of the regulatory action of Bakumondo-to.