Urocortin ameliorates diabetic nephropathy in obese db/db mice

Abstract

Background and purpose: Hyperglycaemia induces overproduction of mitochondrial reactive oxygen species (ROS) in endothelial cells, which is believed to be a major molecular mechanism underlying complications of diabetes, including diabetic nephropathy. Impairment of endothelium-dependent vasodilatation is found in type 2 diabetes. Urocortin is a 40 amino-acid peptide related to the corticotrophin-releasing factor (CRF) family, which suppresses production of ROS in endothelial cells and sustains endothelium-dependent relaxations of rat coronary artery. However, it is not clear if urocortin has any effect on diabetic nephropathy. Experimental approach: Possible mechanisms underlying the effects of urocortin on diabetic nephropathy were investigated in db/db mice and cultured rat mesangial cells. Key results: Urocortin decreased body weight, plasma levels of advanced glycation end-products, blood urea nitrogen and creatinine levels. However, food intake, plasma insulin and glucose levels remained unaffected. Superoxide dismutase activity was increased markedly, whereas malonaldehyde levels in kidney homogenate and sorbitol concentrations in red blood cells were decreased significantly in urocortin-treated mice. Urocortin significantly decreased glomerular extracellular matrix expansion and accumulation in kidney. Moreover, urocortin inhibited the overexpression of transforming growth factor-beta 1 and connective tissue growth factor in rat mesangial cells induced by 25 mM glucose. All the effects of urocortin, except sorbitol accumulation, were abolished by the non-selective CRF receptor blocker, astressin. Conclusion and implications: Urocortin could significantly ameliorate diabetic nephropathy and this effect was mediated via the CRF receptor.

Urocortin 2 protects heart and kidney structure and function in an ovine model of acute decompensated heart failure: Comparison with dobutamine

“…This was associated with significant down-regulation of TGF-β1 -a cytokine considered a key mediator of progressive renal cell injury and fibrosis [32]. Our data is in accord with work in rat mesangial cells showing inhibition of TGF-β1 expression by Ucn (via CRF receptors) [13], while in diabetic rodents, the peptide is reported to decrease kidney TGF-β1 expression in association with reduced glomerular extracellular matrix (ECM) expansion and accumulation, and enhanced creatinine clearance [33]. We also observed Ucn2-suppression of the renal angiotensin system, with decreased angiotensinogen, ACE and AT-1R expression -which is likely to have contributed to attenuation of kidney fibrosis given that angiotensin II (AngII) directly stimulates TGF-β1 secretion in addition to other pro-fibrotic pathways, including aldosterone, and directly induces synthesis of ECM proteins [34].…”

“…Increasing evidence suggests that Ucn2 may antagonize many of the deleterious processes implicated in the underlying pathophysiology of kidney dysfunction in HF, including actions to dilate renal arteries [8] and reduce venous pressure [9], oxidative stress [10], inflammation [11], sympathetic activity [12] and multiple deleterious vasoconstrictor/ pro-fibrotic factors (in particular the renin-angiotensin-aldosterone system [RAAS] and transforming growth factor-β1 [TGF-β1]) [13][14][15]. To date, however, the majority of work investigating Ucn2 in HF has focused on its cardiovascular actions, with little attention directed towards its effects at the kidney.…”

The Corticotropin Releasing Factor System in the Kidney: Perspectives for Novel Therapeutic Intervention in Nephrology

“…According to recent studies in experimental diabetic nephropathy analyzed above, urocortin 1 seems to improve renal function (creatinine levels, creatinine clearance, albuminuria), but also inhibits factors which sustain and aggravate the disease such as TGF‐β1, VEGF, AGEs, polyol pathway, free oxygen radicals, etc . Thereby, urocortin 1 decreases the expansion and accumulation of extracellular matrix which is the characteristic pathological finding in diabetic nephropathy, possibly via secondary mechanisms.…”

“…These are receptor‐mediated actions since they are reversed by the nonselective CRF receptor antagonist astressin. In addition, urocortin 1 improved various laboratory and histological characteristics of diabetic nephropathy in obese, diabetic mice, presumably also by acting on CRF receptors . However, the receptor subtype which is involved remains unknown, since urocortin 1 binds in both receptor types and astressin is a nonselective inhibitor of both of them (Table ).…”

“…Moreover, urocortin 1 inhibited glucose‐induced TGF‐β1 and CTGF (connective tissue growth factor) overexpression in mesangial cell cultures, as all these actions were reversed using astressin, a nonselective CRF‐receptor antagonist. It is therefore very likely that urocortin 1‐mediated inhibition of excessive extracellular matrix production and accumulation in diabetic nephropathy is largely due to suppressed TGF‐β1 and CTGF overexpression . The same group of researchers demonstrated that long‐term intraperitoneal infusion of urocortin 1 in rats with diabetic nephropathy significantly reduced albuminuria, kidneys’ total weight, glomerular TGF‐β and CTGF overexpression, mesangial cell proliferation, and extracellular matrix accumulation.…”