Cyclosporine A (CyA) is an immunosuppressive agent that induces nephrotoxicity with long-term treatment. The roles of DPP-4 and its inhibitors in cyclosporine nephrotoxicity are not fully understood. Therefore, we investigated the effects of a novel DPP-4 inhibitor, DA-1229, on the progression of renal disease in an experimental cyclosporine nephrotoxicity model. Chronic cyclosporine nephrotoxicity was induced in six-week-old male ICR mice by subcutaneous injections of CyA at a dose of 30 mg/kg for four weeks. Animals were treated with DA-1229 at a dose of 300 mg/kg per day in food for four weeks. Although DPP-4 activity did not increase in the kidneys of mice with induced cyclosporine nephrotoxicity, DA-1229 treatment significantly suppressed DPP-4 activity in both plasma and renal tissues. DPP-4 inhibition by DA-1229 led to significantly decreased albuminuria and urinary excretion of 8-isoprosatane. DPP-4 inhibition also substantially suppressed pro-inflammatory effects, profibrotic molecules, and macrophage infiltration, and led to the improvement in renal structural changes. Our results suggest that DPP-4 inhibition by DA-1229 provides renoprotective effects in an animal model of cyclosporine nephrotoxicity via antioxidant, anti-inflammatory, and anti-fibrotic mechanisms. DPP-4 inhibition may be a useful new therapeutic approach for the management of progressive renal disease in cyclosporine nephrotoxicity.

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.

V-set Ig domain-containing 4 (VSIG4) regulates an inflammatory response and is involved in various diseases. However, the role of VSIG4 in kidney diseases is still unclear. Here, we investigated VSIG4 expression in unilateral ureteral obstruction (UUO), doxorubicin-induced kidney injury mouse, and doxorubicin-induced podocyte injury models. The levels of urinary VSIG4 protein significantly increased in the UUO mice compared with that in the control. The expression of VSIG4 mRNA and protein in the UUO mice was significantly upregulated compared with that in the control. In the doxorubicin-induced kidney injury model, the levels of urinary albumin and VSIG4 for 24 h were significantly higher than those in the control mice. Notably, a significant correlation was observed between urinary levels of VSIG4 and albumin (r = 0.912, p < 0.001). Intrarenal VSIG4 mRNA and protein expression were also significantly higher in the doxorubicin-induced mice than in the control. In cultured podocytes, VSIG4 mRNA and protein expressions were significantly higher in the doxorubicin-treated groups (1.0 and 3.0 μg/mL) than in the controls at 12 and 24 h. In conclusion, VSIG4 expression was upregulated in the UUO and doxorubicin-induced kidney injury models. VSIG4 may be involved in pathogenesis and disease progression in chronic kidney disease models.

NADPH oxidase (NOX)-derived oxidative stress is an important factor in renal progression, with NOX4 being the predominant NOX in the kidney. Recently, Src homology 3 (SH3) domain-containing YSC84-like 1 (SH3YL1) was reported to be a regulator of NOX4. In this study, we tested whether the SH3YL1 protein could predict 3-year renal outcomes in patients with type 2 diabetes. A total of 131 patients with type 2 diabetes were enrolled in this study. Renal events were defined as a 15% decline in the estimated glomerular filtration rate (eGFR) from the baseline, the initiation of renal replacement therapy, or death during the 3 years. The levels of the urinary SH3YL1-to-creatinine ratio (USCR) were significantly different among the five stages of chronic kidney disease (CKD) and the three groups, based on albuminuria levels. The USCR levels showed a significant negative correlation with eGFR and a positive correlation with the urinary albumin-to-creatinine ratio (UACR). Plasma SH3YL1 levels were significantly correlated with UACR. The highest tertile group of USCR and plasma SH3YL1 had a significantly lower probability of renal event-free survival. Furthermore, the highest tertile group of USCR showed a significant association with the incidence of renal events after full adjustment: adjusted hazard ratio (4.636: 95% confidence interval, 1.416–15.181, p = 0.011). This study suggests that SH3YL1 is a new diagnostic biomarker for renal outcomes in patients with type 2 diabetes.

Objective This study aims to evaluate the effect of an adaptive nutritional and educational intervention for hemodialysis patients in a routine care setting, using real-world data from electronic health records. Methods Decentralized clinical trial of seven hemodialysis facilities recruited patients under hemodialysis for over 3 months (N=153) for an 8-week adaptive intervention protocol and divided them into four groups: (1) control (2) education intervention (3) meal intervention (4) education and meal interventions. Educational contents are digitally delivered via mobile phones and pre-made meals tailored on laboratory findings via home delivery. Changes in serum electrolytes and malnutrition inflammation score (MIS) are analyzed. Results Meal intervention statistically significantly stabilized serum phosphorus level (β = −0.81) at week 8 with increased likelihood of being in normal range (Odds ratio = 1.21). Meal and education group showed better nutritional status (MIS=3.97) than the control group (MIS=4.57) at week 8 (adjusted p<0.05). No significant changes were observed in serum potassium level, depression, and self-efficacy. Conclusion It is demonstrated that an adaptive education and meal interventions in a real-world care setting may benefit hemodialysis patients’ serum phosphorus control and nutritional status, without negative effect on depression levels or self-efficacy.