Effect of Levosimendan, an Inodilator, on Streptozotocin‐Induced Diabetic Nephropathy in Rats

Abstract

Levosimendan, an inodilator, was shown to have a renal protective effect in different models of kidney dysfunction in experimental animals and in patients with heart failure. The aim of this study was to examine the effect of levosimendan on streptozotocin‐induced early diabetic nephropathy. Male Sprague Dawley rats (n = 24, 320–400 g) were randomly distributed into four groups and treated for 6 weeks. Groups 1 and 3 received either vehicle or levosimendan (1 mg/kg/day) for the last three weeks, respectively. Groups 2 and 4 were rendered diabetic by a single i.p. injection of streptozotocin (60 mg/kg) and were treated as in groups 1 and 3, respectively. At the end of the experiment, rats were placed in metabolic cages and urine was collected for biochemical analysis. Rats were then anesthetized and blood samples collected for biochemical analysis. Kidneys were removed for histopathology. In the untreated diabetic group, there was a significant decrease in body weight, polyuria and increased relative kidney weight. There was increased urinary albumin/creatinine ratio (UACR), 24 hour (h) albumin level and N‐acetyl‐β‐D‐glucosaminidase (NAG)/creatinine ratio (UNCR). Streptozotocin did not cause a significant effect on creatinine clearance when adjusted to body weight. In addition, diabetes was associated with increased oxidative stress [reduced plasma total antioxidant capacity (TAC) and catalase activities]. Kidneys from streptozotocin‐treated rats showed focal clear renal tubular cells affecting proximal convoluted tubules and focal mild interstitial fibrosis at the cortico‐medullary junction. Levosimendan significantly attenuated the reduction in body weight, polyuria and the increase in relative kidney weight. In addition, it significantly attenuated the increase in UACR, urinary 24 h albumin level and UNCR in diabetic rats. It also significantly mitigated the decrease in plasma TAC and catalase activities in diabetic rats. Rats in the diabetic group treated with levosimendan showed less clear cell changes but similar interstitial fibrosis when compared with the untreated diabetic group. This study shows that levosimendan ameliorated some of the changes seen in streptozotocin‐induced early diabetic nephropathy in rats. This could be partly due to its antioxidative effects.Support or Funding InformationSupported by an internal grant from Sultan Qaboos University (IG/MED/PHAR/18/01)