Diabetes mellitus, which is characterized by elevated blood sugar and proceeds with impaired carbohydrate, protein and lipid metabolisms, results from absolute or relative deficiency or ineffectiveness of the insulin hormone which is secreted from the pancreas or structural defects of the insulin molecule
26.
Cases who have had diabetes for a long time suffer from impairments in all vessels. Changes affect both the vascular cells that make up capillaries and arterioles and their basal membranes. Although all microvascular structures are involved, clinically, the pathology occurs only in the retina, renal glomeruli, and major nerves2.
Diabetic nephropathy, in which etiology and pathogenesis has not been clarified yet, is a major cause of end-stage renal failure and the incidence of nephropathy increases with prolonged duration of diabetes27,28. Renal failure is the second most common cause of mortality associated with diabetes after myocardial infarction16.
Although diabetic nephropathy involves structural changes that affect all parts of the kidney, the most characteristic changes have been identified in the glomeruli17.
Oxidative stress refers to a variety of molecular changes resulting from the disturbance of the balance between oxidants and antioxidants in favor of the oxidants in the body18,19. The significance of oxidative stress has been shown particularly in conditions like aging, diabetes, uremia, cardiovascular diseases, malnutrition and cancer20. The balance between pro-oxidants and antioxidants shifts towards oxidative stress in end-stage renal failure (ESRF). Studies about oxidative stress and antioxidants in ESRF patients have recently received increasing attention29.
Growth factors also play a considerable role in the pathogenesis of diabetic nephropathy due to their contributions to functional and structural changes in the development of diabetic kidney disease, as well as their growth-accelerating and proliferative effects. The major growth factors that take a place in diabetic nephropathy include GH, IGF-1, vascular endothelial growth factor, transforming growth factor, epidermal growth factor and platelet-derived growth factor. Of these, the molecules that constitute the GH/IGF system are found in the circulation, extracellular distance and most of the tissues. They serve important functions related to growth27. Research suggests that this system may play a significant role in diabetic nephropathy30.
GH has a place in the development of diabetic microangiopathy. Besides, GH and IGF are believed to play a pathogenic role in diabetic nephropathy21,22. GH was shown to be markedly elevated in the serum of non-obese diabetic mice with induced type-1 diabetes model and rats which had diabetes induced by STZ15,31.
It has also been shown that renal and glomerular hypertrophy and albuminuria could be prevented by GH receptor antagonists in non-obese diabetic mice and mice which had diabetes induced by STZ31,32.
Ghrelin is a peptide-hormone with 28 amino acids, isolated as an endogenous ligand for the Growth Hormone Stimulating Receptor (GHS-R) which stimulated GH secretion both in vivo and in vitro12.
In our study, enalapril and losartan, both of which inhibit oxidation pathways and provide renal protection by reducing proteinuria, were administered to rats which had experimental diabetes induced by STZ, and their ghrelin immunoreactivity was observed5-8. Ghrelin immunoreactivity in the renal cortex and medulla of both groups which were administered enalapril and losartan was found moderate (++) similar to the immunoreactivity found in the controls. Likewise, moderate (++) ghrelin immunoreactivity was observed in the distal tubules. However, the diabetic group had severe (+++) ghrelin immunoreactivity in the renal cortex, medulla and distal tubules.
Masaoka et al15 induced diabetes with STZ in Wistar rats. They established a significant decrease in serum insulin and IGF-1 levels and a marked increase in serum GH, serum total and active ghrelin levels. They attributed the elevated plasma ghrelin concentration to ghrelin immunoreactive stomach cells, but they also suggested as a possibility that ghrelin synthesis might have increased in an organ other than the stomach in diabetes.
Mice which had been subjected to bilateral nephrectomy and partial nephrectomy were found to have increased levels of plasma total ghrelin, but were not found to have any increase in either the ghrelin mRNA levels or ghrelin content in the stomach. Therefore, the concerned increase may be due to a decrease in the renal clearance or destruction of ghrelin25.
Mori et. al.23 who were the first to demonstrate the prepro-ghrelin gene expression in the mouse kidney, besides the gastrointestinal system and the brain, argued that ghrelin could be locally produced in the kidney and also that ghrelin could play endocrine and/or paracrine roles in this organ. Kuloğlu et. al.24 showed in their study that ghrelin immunoreactivity increased in proportion to the length of diabetes in the distal tubules of renal cells of rats with experimentally induced diabetes.
Ghrelin is filtered through the distal tubule epithelium and blood. It is actively secreted through the urine. The urine was found to contain more ghrelin than the amount of ghrelin in the circulation25.
Enalapril which acts upon the reactive oxygen system reduces free radicals. In the same way, ghrelin may decrease the levels of free radicals as it eliminates free radicals33. Küçüksu33 argued in his study that, as both ghrelin and enalapril sweep away oxidative stress through similar pathways, enalapril use reduced the level of ghrelin by blocking the balancing mechanism that ghrelin offers. In our study, we also think that enalapril and losartan molecules may be interacting with ghrelin in the same way. Therefore, we are of the opinion that use of enalapril and losartan in diabetes may affect the ghrelin expression of distal tubules in a manner that is similar to the one in the control group.
In conclusion, we believe that enalapril and losartan administration is effective in the expression of ghrelin in the renal tissue of diabetic rats and that more extensive studies are needed on this topic.
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