GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases

Abstract

Accumulating evidence has implicated that GLP-1 may have a beneficial effect on cardiovascular and renal diseases but the mechanism is not fully understood. Here we show that GLP-1 analog, liraglutide, inhibits oxidative stress and albuminuria in streptozotocin (STZ)-induced type 1 diabetes mellitus rats, via a protein kinase A (PKA)-mediated inhibition of renal NAD(P)H oxidases. Diabetic rats were randomly treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Oxidative stress markers (urinary 8-hydroxy-2'-deoxyguanosine and renal dihydroethidium staining), expression of renal NAD(P)H oxidase components, transforming growth factor-β (TGF-β), fibronectin and urinary albumin excretion were measured. In vitro effect of liraglutide was evaluated using cultured renal mesangial cells. Administration of liraglutide did not affect plasma glucose levels or body weights in STZ diabetic rats, but normalized oxidative stress markers, expression of NAD(P)H oxidase components, TGF-β, fibronectin in renal tissues and urinary albumin excretion, all of which were significantly increased in diabetic rats. In addition, in cultured renal mesangial cells, incubation with liraglutide for 48 h inhibited NAD(P)H-dependent superoxide production evaluated by lucigenin chemiluminescence in a dose-dependent manner. This effect was reversed by both PKA inhibitor H89 and adenylate cyclase inhibitor SQ22536, but not by Epac2 inhibition via its small interfering RNA. Liraglutide may have a direct beneficial effect on oxidative stress and diabetic nephropathy via a PKA-mediated inhibition of renal NAD(P)H oxidase, independently of a glucose-lowering effect.

Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy

“…These effects were accompanied by downregulation of TGFB1 expression, decreased collagen type IV accumulation, suppressed inflammation, reduced apoptosis and lower oxidative stress (Park et al 2007). In alignment with these findings, many other studies also revealed renal beneficial effects of GLP-1 analogues in animal models of diabetic nephropathy suggesting many mechanisms behind these effects such as cAMPprotein kinase A pathway activation, inhibition of renal NAD(P)H oxidases (Hendarto et al 2012, Fujita et al 2014a, downregulation of AGE-induced protein arginine methyltranferase-1 expression (Ojima et al 2013), decreased ICAM-1 production, reduced release of proinflammatory cytokines from macrophages (Kodera et al 2011) and up-regulation of ATP-binding cassette transporter A1 (ABCA1) in glomerular endothelial cells, which promoted cholesterol efflux from cells and blocked inflammatory responses (Yin et al 2016). Moreover, the natriuretic and diuretic effects of GLP-1 analogues and DPP-4 inhibitors through interaction with Na + /H + exchanger isoform 3 could play a role regarding their reno-protective effects.…”

Molecular and cellular mechanisms of glucagon-like peptide-1 receptor agonist-mediated attenuation of cardiac fibrosis

“…Liraglutide treatment significantly attenuated cardiac superoxide production (Figure 8) identifying an additional component of the potential molecular mechanism responsible for attenuation of cardiac fibrosis by liraglutide in our murine models and supporting several pre-clinical studies. [38][39][40][41] Our study is the first to evaluate the potential beneficial effects of a GLP-1R agonist in an ageing model of cardiac fibrosis with restitution of fibrosis to levels demonstrated in 'young' 5-month-old mice in aged mice treated with liraglutide (Figure 4(b)). The unique characteristics associated with age-induced cardiac fibrosis include direct senescence-associated fibrogenic actions and impaired responses to cardiac damage including a reduced capacity to degrade collagen.…”

Once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide is non‐inferior to once‐daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26‐week randomized phase III study

“…These pleiotropic effects might be a class effect of GLP‐1 receptor agonists. A recent report showed that liraglutide protected against albuminuria in streptozotocin‐induced diabetic rats in a protein kinase A‐mediated manner, which was not related to lowered glucose levels 27. Meier et al.…”