The presence of galectin-9 in human serum was well-documented in previous reports. Serum galectin-9 was elevated in hepatitis C infection and it was released from Kupffer cells in the liver . In addition, oral administrations of dietary synbiotic bacteria such as Bifidobacterium breve M-16V increased the expression of galectin-9 in intestinal epithelial cells, increased serum galectin-9 levels, and prevented allergic responses in human . Galectin-9 is also stimulated and released from various cells by interferon-γ in human endothelial cells , fibroblasts , pancreatic β cells , and Kupffer cells . Galectin-9 is vulnerable to digestion by proteolytic degradation; however, it was reported that galectin-9 is inserted into exosome and released, thus it is protected by enzymatic degradation, and the intact 36 kDa molecule was demonstrated in the serum exosome fraction . Galectin-9 is also abundantly expressed in the cytoplasm of tubular cells and kidney may contribute the circulating Gal-9; however, regulation of the release of Gal-9 from kidney cells is completely unknown [2, 3].
In current clinical investigation, simple correlation of Log10Gal-9 levels with age, Cr, UN, and eGFR suggested that serum Gal-9 levels closely related to the renal function in patients with type 2 diabetes. The molecular weight of Gal-9 is ~36 kDa and it would be filtered through glomerular capillaries and the reduction of GFR may be linked to the elevation of serum Gal-9 levels. Actually, log10Gal-9 levels increased along with the progression of GFR stages, i.e. G1 to G4. In diabetic kidney disease, albuminuria also increased during the progression of the disease and Gal-9 may be actively filtered through glomerular basement membranes; however, serum Gal-9 levels did not negatively correlate with urinary albumin excretion and serum Gal-9 levels were not altered in the progression of albuminuria stages from A1 to A3. Although both of the reduced filtration of Gal-9 and loss of Gal-9 into the urine may be the determinants for the serum Gal-9 levels, the current clinical study suggested that GFR mainly defined the serum Gal-9 levels.
In addition to GFR, serum Gal-9 levels also revealed simple correlation with osmotic pressure. Since serum osmotic pressure is determined by the concentrations of sodium, potassium, plasma glucose and UN, the osmotic pressure in the patients of type 2 diabetes would be elevated by the impairment of renal function or by hyperglycemia. Multiple linear regression analysis revealed that osmotic pressure is only significant predictor for serum Gal-9 levels by employing age, osmotic pressure and eGFR as independent variables. A novel model for non-classical secretion of fibroblast growth factor 1 (FGF1), FGF2, and galectins without signal peptide have been reported, namely oncotic release, where a change in the colloidal osmotic pressure by serum deprivation in the culture cells creates the nonlethal oncotic pores in the plasma membranes through which proteins are released . There are no reports whether the increase in osmotic pressure alters the plasma membrane and it stimulates the secretion of Gal-9 via non-classical pathway; however, the current study suggested that osmotic pressure might be the stimulator for the release of Gal-9 and the future studies are required to support this evidence.
Since the current investigation is cross-sectional clinical study, it is difficult to conclude whether elevated serum Gal-9 levels are protective or promoting for the progression of diabetic nephropathy. Gal-9 induces apoptosis in CD4+Tim-3+ TH1 cells, and Gal-9-Tim-3 pathway negatively regulates TH1 immunity, thus the elevation of serum Gal-9 may be beneficial in the progression of diabetic nephropathy by negatively regulating the immune responses and inflammation . In addition, the elevation of serum Gal-9 concentrations may inhibit the G1 cell cycle arrest and hypertrophy of the kidney cells . Thus, the follow-up cohort study may be required to clarify whether the elevated serum Gal-9 levels in type 2 diabetes are preventive for the progression of diabetic nephropathy. In recent series of the investigations, Gal-9 is also reported to regulate the virus specific T-cell response , T cell immunity in hepatitis C infection , anti-microbial immunity , it is an important clinical question whether elevated serum levels of Gal-9 in the patients with type 2 diabetes and diabetic nephropathy are related to the susceptibility for various infection in the future studies.