Studies On The Protective Effect Of Apelin On The Pancreatic And Renal Injury

Diabetes, characterized by long-term high blood glucose, is a metabolic disease with insulin secretion disorder and/or insulin function disorder. Diabetic chronic hyperglycemia may cause organ dysfunction and failure, and induce various complications of diabetes. Diabetic nephropathy, a common microvascular complication of diabetes, is characterized by glomerular sclerosis and nephrotic syndrome, which is also considered to be the primary cause of end-stage renal failure. Obese diabetic nephropathy is often accompanied with renal ischemia/reperfusion (I/R) injury. So far, the molecular mechanisms, prevention and treatments for diabetes, diabetic nephropathy and renal I/R injury remain unclear. Apelin, a newly identified bioactive adipokine, has been found to play important roles in regulation of blood pressure, insulin secretion and energy metabolism. Apelin-13is the most abundant and active member of the apelin family. Here, we investigated whether apelin-13could effectively inhibit the development of diabetes induced pancreas and kidney lesions, and suppress the renal I/R injury.We used Akita mice as a type1diabetic animal model to study the development of diabetic pancreas and kidney lesions. High glucose medium stimulated HBZY-1and MES13cells were used as an in vitro model of diabetic nephropathy. Wistar rats with unilateral renal ligation were used as the animal model of renal ischemia/reperfusion injury. The HBZY-1and NRK-52E cells cultured in serum-free and glucose-free medium under hypoxia (1%O2) conditions were used as an in vitro model of renal I/R injury. We studied the therapic effect of apelin with focus on the lesions of pancreas and kidney on the molecular, cellular, and pathologic levels via Western blot, immunohistochemistry, immunofluorescence staining, polymerase chain reaction and chromatin immunoprecipitation experiment techniques.The results obtained from the mice after two months tail vein injection of apelin-13suggested the treatment significantly increases islet area and insulin content in the pancreas of Akita mice. Further studies suggested apelin-13treatment alleviates ER stress by inhibiting the diabetes induced up-regulation of PERK and IRE1α and chaperones (GRP78, calnexin and Hsp70) levels, and normalizes the diabetes induced alteration of AKT and ERK activations in the pancreas of Akita mice.Secondly, apelin-13treatment decreased diabetes-induced glomerular filtration rate, proteinuria, glomerular hypertrophy, mesangial expansion and renal inflammation. The inflammatory factors, activation of NF-κB, histone acetylation and the enzymes involved in histone acetylation were further examined in diabetic kidneys and high glucose or sodium butyrate (NaB) treated mesangial cells in the presence or absence of apelin-13. Apelin-13treatment inhibited diabetes-or high glucose-or NaB-induced elevation of inflammatory factor, histone hyperacetylation by upregulation of histone deacetylases1(HDAC1). In addition, apelin-13treatment significantly decreased the tubular necrosis, apoptosis and renal inflammation in the process of kidney I/R injury. Apelin alleviated I/R injury induced Tgf-P, histone hypermethylation and apoptosis in the kidneys of wistar rats. Moreover, apelin also ameliorated I/R induced Tgf-P, histone hypermethylation and apoptosis in HBZY-1and NRK-52E cells under hypoxia condition.Taken together, these results suggest apelin not only alleviates pancreas and kidney lesions in type1diabetes, but also inhibites the procession of kidney I/R injury. The results suggested that apelin-13alleviates diabetes induced endoplasmic reticulum stress, increases the expression of insulin in the pancreas of Akita mouse. And apelin-13could reduce diabetes induced histone hyperacetylation, and inhibit the activation of NF-κB and MAPK pathways. Apelin-13also significantly suppressed inflammatory response in the kidney of Akita mouse. In addition, apelin-13also can inhibit ischemia/reperfusion injury induced Tgf-P pathway and histone hypermethylation, and finally inhibits apoptosis. All these results indicate apelin-13not only has a good therapeutic effect on type1diabetes and diabetic nephropathy, but also shows evident curative effect on acute renal injury. This work provides guidance to explore the molecular mechanism of acute kidney injury, diabetes and diabetic nephropathy, and a new research direction for drug candidate for acute kidney injury, diabetes and diabetic nephropathy.