Kallistatin protects against diabetic nephropathy in db/db mice by suppressing AGE-RAGE-induced oxidative stress

Abstract

Kallistatin is a serine protease inhibitor with anti-inflammatory, anti-angiogenic, and anti-oxidative properties. Since oxidative stress plays a critical role in the pathogenesis of diabetic nephropathy, we studied the effect and mechanisms of action of kallistatin superinduction. Using ultrasound-microbubble-mediated gene transfer, kallistatin overexpression was induced in kidney tubules. In db/db mice, kallistatin overexpression reduced serum creatinine and BUN levels, ameliorated glomerulosclerosis and tubulointerstitial injury, and attenuated renal fibrosis by inhibiting TGF-β signaling. Additionally, downstream PAI-1 and collagens I and IV expression were reduced and kallistatin partially suppressed renal inflammation by inhibiting NF-κB signaling and decreasing tissue kallikrein activity. Kallistatin lowered blood pressure and attenuated oxidative stress as evidenced by suppressed levels of NADPH oxidase 4, and oxidative markers (nitrotyrosine, 8-hydroxydeoxyguanosine, and malondialdehyde) in diabetic renal tissue. Kallistatin also inhibited RAGE expression in the diabetic kidney and AGE-stimulated cultured proximal tubular cells. Reduced AGE-induced reactive oxygen species generation reflected an anti-oxidative mechanism via the AGE-RAGE-reactive oxygen species axis. These results indicate a renoprotective role of kallistatin against diabetic nephropathy by multiple mechanisms including suppression of oxidative stress, anti-fibrotic and anti-inflammatory actions, and blood pressure lowering.

The Potential Role of Kallistatin in the Development of Abdominal Aortic Aneurysm

“…Oxidative stress has been shown to suppress circulating levels of kallistatin and EC specific expression of kallistatin [52,53], while kallistatin has been shown to suppress ROS production in cardiac and renal cells [45,54]. Many studies have suggested that kallistatin has anti-oxidative stress functions through inhibiting NADPH oxidase activities in various cell types, such as cardiac, epithelial progenitor cells (epi-PCs) and endothelial progenitor cells (endo-PCs), as well as in experimental models of myocardial infarction, hypertension and diabetes in rodents [44,54,55,56]. Furthermore, administration of anti-kallistatin antibody to rats has been reported to increase superoxide formation within the aorta and increased NADPH activity in the kidney and heart which eventually led to organ hypertrophy, inflammation and fibrosis.…”

Rodent models of diabetic nephropathy: their utility and limitations

“…43,44 Additionally, numerous studies have reported oxidative stress and inflammation in the kidneys of db/db mice. 44,47,48 However, db/db mice do not develop mesangiolysis, nodular mesangial sclerosis, or severe tubulointerstitial fibrosis, which are features of advanced diabetic nephropathy in humans. They also do not develop progressive renal insufficiency.…”

Genetic variants in SERPINA4 and SERPINA5, but not BCL2 and SIK3 are associated with acute kidney injury in critically ill patients with septic shock

“…Of note, it may also have a renoprotective role against diabetic nephropathy [24]. rs1955656 in SERPINA5 is strongly correlated with rs2093266 and as suspected before, this association with AKI could be driven by rs2093266.…”