Upregulation of VSIG4 in Type 2 Diabetic Kidney Disease

Abstract

Fibrosis is the final common finding in patients with advanced diabetic kidney disease. V-set Ig domain containing 4 (VSIG4) is related to fibrosis in several diseases. It also contributes to fibrosis under high-glucose conditions in renal tubule cells. To determine the role of VSIG4 in type 2 diabetes, we examined VSIG4 expression in a type 2 diabetic animal model and podocyte. Urinary excretion of albumin and VSIG4 was significantly higher in db/db mice than in the control group. Urine VSIGs levels for 6 h were about three-fold higher in db/db mice than in db/m mice at 20 weeks of age: 55.2 ± 37.8 vs. 153.1 ± 74.3 ng, p = 0.04. Furthermore, urinary VSIG4 levels were significantly correlated with urinary albumin levels (r = 0.77, p < 0.01). Intrarenal VSIG4 mRNA expression was significantly higher in db/db mice than in control mice (1.00 ± 0.35 vs. 1.69 ± 0.77, p = 0.04). Further, VSIG4 expression was almost twice as high in db/db mice at 20 weeks of age. Intrarenal VSIG immunoreactivity in db/db mice was also significantly higher than that in control mice. In cultured podocytes, both high glucose and angiotensin II significantly upregulated the expression of VSIG4 mRNA and protein. In conclusion, VSIG4 was upregulated in an animal model of type 2 diabetes and was related to albuminuria and pro-fibrotic markers. Considering these relationships, VSIG4 may be an important mediator of diabetic nephropathy progression.

Keywords: VSIG4; diabetes; fibrosis; kidney.

Figure 1

Urinary VSIG4 level and its correlation with albuminuria in db/m (n = 6) and db/db (n = 6) mice. (a) Urinary VSIG4 level for 6 h at 8, 12, and 20 weeks of age. (b) Correlation between urinary VSIG4 levels and albuminuria. Blue: db/m mice, red: db/db mice. * p < 0.05 vs. db/m.

Figure 2

Serum VSIG4 levels in db/m (n = 6) and db/db (n = 6) mice.

Figure 3

Intrarenal mRNA expression of VSIG4 and profibrotic markers in db/m (n = 6) and db/db (n = 6) mice. Black bars indicate mean value. * p < 0.05 vs. db/m mice.

Figure 4

Immunohistochemical staining of VSIG4 in db/m (n = 6) and db/db (n = 6) mice. (a) Representative histologic findings of intrarenal VSIG4 protein expression. (b) Semiquantitative expression of VSIG4 in proximal and distal tubules. * p < 0.05 vs. db/m mice.

Figure 5

Expression of VSIG4 and profibrotic markers in podocytes stimulated with high glucose (HG) and angiotensin II (Ang II). (a) mRNA expression of each marker; (b) representative protein expression by Western blot. Values are expressed as mean ± SD. * p < 0.05 vs. normal glucose (NG).