辻 雄大

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide with most patients progressing to kidney failure. Although its pathophysiology remains incompletely understood, deposition of IgA-containing immune complexes in the glomerular mesangium induces mesangial cell proliferation and overproduction of extracellular matrix components and cytokines and chemokines, that lead to glomerular injury. The properties of nephritogenic IgA1 include abnormal glycosylation of its polymeric forms and its capacity to bind IgG autoantibodies to form immune complexes. Nephritogenic IgA1 is thought to be secreted by B cells originating from or residing in mucosa-associated lymphoid tissues (MALT), such as gut-associated lymphoid tissues (GALT) and nasopharynx-associated lymphoid tissues (NALT). However, little is known how the immune abnormalities in MALT elevate the circulatory levels of nephritogenic IgA. This review summarizes fundamental insights into IgA production and its regulation in MALT in general, provides an overview of the immune abnormalities in the MALT of patients with IgAN relevant to the production of abnormally glycosylated IgA, and summarizes relevant emerging treatments tested in clinical trials.

PURPOSE: Recent studies have reported that sodium-glucose cotransporter (SGLT) 2 inhibitors ameliorate steatotic liver disease. We investigated the contribution of SGLT2 inhibitor-induced fluid loss due to glycosuria in hepatic ureagenesis for water conservation to the association between improvement of steatotic liver disease and the energy-consuming nature of hepatic ureagenesis. GENERAL METHODS: ob/ob mice fed a high-fat diet without carbohydrate restriction were administered luseogliflozin, an SGLT2 inhibitor, for eight weeks. FINDINGS: Luseogliflozin significantly decreased the liver weight, plasma aspartate aminotransferase and alanine aminotransferase levels, and fat content in mice with enhanced glycosuria (H-GlcV group). The ratio of urinary urea excretion decreased as a substitute for increased glucose excretion in the H-GlcV group. Luseogliflozin significantly increased liver urea content and tended to increase malate dehydrogenase (MDH)-1 activity. Liver MDH-1 activity was significantly positively correlated with liver urea content, suggesting that MDH-1-induced amino acid recruitment from the tricarboxylic acid cycle to the urea cycle may contribute to enhanced ureagenesis. In addition, liver weight was significantly negatively correlated with the liver urea content. CONCLUSIONS: Our data suggest that enhanced hepatic ureagenesis as a compensatory water conservation mechanism for glycosuria-induced fluid loss may be associated with amelioration of steatotic liver disease in SGLT2 inhibitor-treated ob/ob mice.

Structural variations of N-glycans critically regulate glycoprotein functions and are involved in various human diseases. N-Acetylglucosaminyltransferase-III (GnT-III or MGAT3) is highly expressed in the brain and kidney and is an N-glycan branching enzyme that biosynthesizes the unique N-glycan branch designated as bisecting GlcNAc. Its roles in Alzheimer's disease and cancer have been revealed, but the functions of bisecting GlcNAc in the kidney are poorly understood. Here, we show that kidneys in the GnT-III-knockout (KO) mouse exhibit impaired body fluid balance and present interstitial edema. To understand the molecular mechanisms further, we biochemically purified the glycoproteins modified by GnT-III in the mouse kidney and identified these proteins using proteomics. We found that the proteins involved in the pathway for angiotensin II (Ang II) metabolism are modified by GnT-III, and that the subcellular localization of angiotensin-converting enzyme was altered in GnT-III-KO cells. Furthermore, the pathology in models of Ang II-related disease was slightly more severe in GnT-III-KO than in wild-type mice. Our data indicate a protective role for bisecting GlcNAc in the mouse kidney, highlighting a newly described link between specific N-glycan structures and renal functions.