Exogenous activated protein C inhibits the progression of diabetic nephropathy

Abstract

Summary. Background: Activated protein C (APC) can regulate immune and inflammatory responses and apoptosis. Protein C transgenic mice develop less diabetic nephropathy but whether exogenous administration of APC suppresses established diabetic nephropathy is unknown. Objectives: We investigated the therapeutic potential of APC in mice with streptozotocin‐induced diabetic nephropathy. Methods: Diabetes was induced in unilaterally nephrectomized C57/Bl6 mice using intraperitoneal (i.p.) injection of streptozotocin. Four weeks later, the mice were treated with i.p. exogenous APC every other day for 1 month. Results: APC‐treated mice had a significantly improved blood nitrogen urea‐to‐creatinine ratio, urine total protein to creatinine ratio and proteinuria, and had significantly less renal fibrosis as measured by the levels of collagen and hydroxyproline. The renal tissue concentration of monocyte chemoattractant protein‐1 (MCP‐1), vascular endothelial growth factor (VEGF) and the RNA expression of platelet‐derived growth factor (PDGF), transforming growth factor‐β1 and connective tissue growth factor (CTGF) were significantly lower in APC‐treated mice than in untreated animals. The percentage of apoptotic cells was reduced and the expression of podocin, nephrin and WT‐1 in the glomeruli was significantly improved in mice treated with APC compared with untreated mice. The levels of coagulation markers were not affected by APC treatment. Conclusion: Exogenous APC improves renal function and mitigates pathological changes in mice with diabetic nephropathy by suppressing the expression of fibrogenic cytokines, growth factors and apoptosis, suggesting its potential usefulness for the therapy of this disease.

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 Shc

“…Epigenetic control of gene expression may explain the profound effects of intermittently administered exogenous aPC in various animal models despite its half-life of only ∼25 min (4,6). aPC suppressed expression of p66 Shc at concentrations as low as 2 nM, which is ∼100-fold lower than the concentrations of aPC previously used by Yamaji et al (5) to study the antioxidant H3 acetylation within the p66 Shc promoter is induced by glucose and prevented by aPC (2 nM).…”

“…injections of aPC ameliorated diabetic nephropathy without improving blood glucose levels ( Fig. S1 A and B) (6). In addition to reducing FMA, treatment with exogenous aPC decreased glomerular nitrotyrosine formation ( Fig.…”

“…7), in which aPC suppressed lipopolysaccharide-induced reactive oxygen species (ROS) generation and NF-κB binding activity (5). The potential relevance of the antioxidant properties of aPC is further supported by its potent nephroprotective effects in a mouse model of diabetic nephropathy (6,7). Mitochondrial dysfunction resulting in the generation of ROS is considered to be a unifying mechanism underlying diabetic vascular complications, including diabetic nephropathy (8,9).…”

Amelioration of Diabetes by Protein S

“…On the third week after STZ or saline injection, an intraperitoneal glucose tolerance (IPGT) test was performed after 16 h of fasting by intraperitoneal injection of glucose (1 g/kg mouse body weight), and tail vein blood was sampled on days 0, 7, 14, 21, and 28 for glycemia measurement. An insulin sensitivity test was (15). Control (hPS/SAL, WT/SAL) mice received intraperitoneally similar amounts of saline.…”

“…Mice were killed 8 weeks after the last STZ or saline injection. In separate experiments, WT mice underwent unilateral nephrectomy, received intraperitoneally injected STZ or saline for 5 consecutive days after 4 weeks of recovery, and were then treated with either hPS or saline subcutaneously through osmotic minipumps for 4 weeks before they were killed (15).…”