OP27 H2S and heme oxygenase: A possible co-operation against diabetic nephropathy

Abstract

Background Diabetic nephropathy (DN) is one of the most common microvascular complications of Type 1 diabetes and it is the main cause of end-stage renal failure in Western Societies. Several factors contribute to the onset of DN including hypertension and hyperglycaemia induced oxidative stress. The antioxidant enzyme heme oxygenase (HO) plays a key role in the protection against oxidative stress. HO is the rate limiting enzyme in the degradation of heme: the products of the reaction, CO 2 , free iron and bilirubin, have anti-oxidant, anti-inflammatory and anti-apoptotic properties. In humans HO exists as two isoforms. Heme oxygenase-1 (HO-1) is the inducible isoform and it is expressed under stress and pathological conditions and has anti-inflammatory, anti-apoptotic and anti-oxidant properties. Heme oxygenase-2 (HO-2) is the constitutive isoform and it is generally expressed to degrade heme. Hydrogen sulfide (H 2 S) has been shown to be produced in the kidneys and it is involved in several physiological functions controlling vascular, renal functions, blood pressure, and it can be considered a powerful reducing agent as it can neutralize oxidant species like superoxide and hydrogen peroxide. H 2 S has also been claimed to be involved in several diseases such as cardiovascular diseases, hypertension, and ischemia injury and also in inflammation. Lower levels of H 2 S have been found in patients with chronic kidney diseases, diabetes and obesity. It is also thought that H 2 S may retard the progression of DN as the administration of exogenous H 2 S lowers blood pressure and reduces hypertension in diabetic rats. Aim To understand the role that H 2 S and HO have in the protection against oxidative stress and therefore in the development of DN and to identify a possible connection between them. Methods Two different kidney cell lines were used: human mesangial cells (HMCs), and podocytes. The cells were treated with different H 2 S donors for different times and different concentrations, then the protein levels of both HO-1 and HO-2 were analysed by Western blot. Results HO-1 responded in the same way in both HMCs and podocytes. In fact, when the cells were treated for 24 h with different H 2 S donors there was an increase in the protein levels. However, treatments shorter than 24 h did not have any effect on HO-1 expression. The expression of HO-2 in podocytes and HMCs was not altered following any of the treatments with the donors. Conclusions Only HO-1 seems to respond to the H 2 S donors suggesting there is an interaction between HO-1 and H 2 S but not between HO-2 and H 2 S; it is possible that the two isoforms are involved in different mechanisms and therefore they respond in different ways to increased H 2 S. Both H 2 S and HO-1 are believed to have protective roles in the cells so it is possible that both systems co-operate to preserve the cells under stress conditions. They might both be involved in the development of diabetic nephropathy so in future they might be considered as therapeutic agent to slow down this condition.