Molecular Mechanisms Underlying the Nephroprotective Effects of PACAP in Diabetes (original) (raw)
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Effect of PACAP treatment on kidney morphology and cytokine expression in rat diabetic nephropathy
Peptides, 2013
Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide, exerting diverse effects. One of its frequently examined functions is cell protection, which is achieved mainly via inhibiting apoptotic, inflammatory and oxidative processes. All its three receptors (PAC1, VPAC1, VPAC2) are expressed in the kidney and PACAP has been shown to have protective effects against different renal pathologies. Diabetic nephropathy is the leading cause of end stage renal disease. The aim of the present study was to investigate the possible ameliorative effect of PACAP in streptozotocin-induced diabetic nephropathy and to evaluate its anti-inflammatory effect in this model. Diabetes was induced by a single intravenous injection of streptozotocin (65 mg/kg) in male Wistar rats. PACAP-treated animals were administered ip. 20 g PACAP every second day, while untreated animals were given vehicle. Kidneys were removed after 8-weeks survival. Besides the complex histological analysis (glomerular PAS positive area/glomerulus area, tubular damage, arteriolar hyalinosis), expression of several cytokines was evaluated by cytokine array and Luminex assay. Histological analysis revealed severe diabetic changes in kidneys of control diabetic animals (glomerular PAS-positive area expansion, tubular damage, Armanni-Ebstein phenomenon). PACAP treatment significantly diminished the damage. Diabetic kidneys showed significant cytokine activation compared to their healthy controls. PACAP was effective in downregulation of several cytokines including CINC-1, TIMP-1, LIX, MIG, s-ICAM. To conclude, PACAP is effective in ameliorating diabetic nephropathy at least partly through its well-known anti-inflammatory effect. These results raise the opportunity for the use of PACAP as a possible therapeutic or preventive method in treating the complications of diabetes.
Emerging Role of PACAP as a New Potential Therapeutic Target in Major Diabetes Complications
International journal of endocrinology, 2015
Enduring diabetes increases the probability of developing secondary damage to numerous systems, and these complications represent a cause of morbidity and mortality. Establishing the causes of diabetes remains the key step to eradicate the disease, but prevention as well as finding therapies to ameliorate some of the major diabetic complications is an equally important step to increase life expectancy and quality for the millions of individuals already affected by the disease or who are likely to develop it before cures become routinely available. In this review, we will firstly summarize some of the major complications of diabetes, including endothelial and pancreatic islets dysfunction, retinopathy, and nephropathy, and then discuss the emerging roles exerted by the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) to counteract these ranges of pathologies that are precipitated by the prolonged hyperglycemic state. Finally, we will describe the main signallin...
DIABETIC NEPHROPATHY -GENESIS, PREVENTION AND TREATMENT Review Article
International journal of Pharmacy and Pharmaceutical Sciences, 2014
Diabetic Nephropathy (DN) is the foremost reason of End Stage Renal Disease (ESRD) and a major cause of premature deaths amongst people with diabetes. It is one of the most common complications of diabetes mellitus (DM) and has majorly influenced patients' morbidity and mortality. About 50% of patients suffering from DM for more than 20 years develop this complication. The present review focuses on the global scenario of diabetic nephropathy and different molecular mechanisms involved in its pathogenesis i. e. increased formation of advanced glycation end products (AGEs), enhanced glucose flux into polyol and hexosamine pathways, activation of protein kinase C (PKC) and other proinflammatory transcription factors. This review also highlights the precautionary measures to be taken by people with diabetes along with the therapeutic interventions involving angiotensin converting enzyme (ACE) inhibitors, renin inhibitors, angiotensin receptor antagonists, aldosterone antagonists, protein kinase C inhibitors, mechanistic target of rapamycin (m-TOR) inhibitors, agents inhibiting plasminogen activator inhibitor-1 (PAI-1), advanced glycation end products inhibitors, anti-inflammatory agents and antioxidant agents.
The Missing Link in Diabetic Nephropathy?
2010
Proinsulin C-peptide has been found to exert beneficial effects in many tissues affected by diabetic microvascular complications, including the kidneys. Glomerular hyperfiltration and microalbuminuria are early markers of diabetic nephropathy. C-peptide at physiological concentrations effectively reduces diabetes-induced glomerular hyperfiltration via constriction of the afferent arteriole, dilation of the efferent arteriole, and inhibition of tubular reabsorption in experimental models of type 1 diabetes. The glomerular hypertrophy and mesangial matrix expansion seen in early diabetes can be reduced or prevented by C-peptide administration, possibly via interference with TGF-β1 and TNFα signaling. Several of C-peptide’s reno-protective effects have been confirmed in human studies; reduced glomerular hyperfiltration and diminished urinary albumin excretion have been documented in type 1 diabetes patients receiving replacement doses of C-peptide for periods of up to 3 months. In this...
Endocrinology, 2009
This study was aimed at evaluating the role for poly(ADP-ribose) polymerase (PARP) in early nephropathy associated with type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with one of two structurally unrelated PARP inhibitors, 1,5isoquinolinediol (ISO) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo [de] anthracen-3-one (GPI-15427), at 3 mg/kg Ϫ1 ⅐ d Ϫ1 ip and 30 mg/kg Ϫ1 ⅐ d Ϫ1 , respectively, for 10 wk after the first 2 wk without treatment. PARP activity in the renal cortex was assessed by immunohistochemistry and Western blot analysis of poly(ADP-ribosyl)ated proteins. Variables of diabetic nephropathy in urine and renal cortex were evaluated by ELISA, Western blot analysis, immunohistochemistry, and colorimetry. Urinary albumin excretion was increased about 4-fold in diabetic rats, and this increase was prevented by ISO and GPI-15427. PARP inhibition counteracted diabetesassociated increase in poly(ADP-ribose) immunoreactivities in renal glomeruli and tubuli and poly-(ADP-ribosyl)ated protein level. Renal concentrations of TGF- 1, vascular endothelial growth factor, endothelin-1, TNF-␣, monocyte chemoattractant protein-1, lipid peroxidation products, and nitrotyrosine were increased in diabetic rats, and all these changes as well as an increase in urinary TNF-␣ excretion were completely or partially prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-induced up-regulation of endothelin (B) receptor, podocyte loss, accumulation of collagen-␣1 (IY), periodic acid-Schiff-positive substances, fibronectin, and advanced glycation end-products in the renal cortex. In conclusion, PARP activation is implicated in multiple changes characteristic for early nephropathy associated with type 1 diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies.
Nephrology Dialysis Transplantation, 2012
Introduction and Aims: The renin-angiotensin system (RAS) plays pivotal roles on progression of diabetic nephropathy. However, much remains unknown about the molecular mechanisms involved. The aim of the study was to obtain novel insights into the processes by systemic transcriptome analysis by DNA microarray technology. Methods: RNA was extracted from a small part of renal cortical biopsy specimens. A total number of 54,675 transcripts expression levels were analyzed systemically with GeneChip Human Genome U133 Plus 2.0 Array (Affymetrix). Specific gene clusters involved in diabetic nephropathy was analyzed by hierarchical clustering method. Extracted candidate genes were analyzed by real-time PCR method with LightCycler (Roche). Results: Hierarchical clustering analysis with 18 samples showed cluster formation considerably distinct by each original renal condition. By a hierarchical clustering analysis with 3 samples each from minor abnormality and diabetic nephropathy, we divided the transcripts to 12 clusters. By ontology and pathway analysis from the 11th cluster, the renin-angiotensin system was selected as a diabetic nephropathy specific pathway implying the reduction of ACE2, C9orf3, ENPEP and AT4/IRAP, which are thought to exert the effects for degradation of angiotensin II. Further analysis of 78 subjects with real-time PCR method revealed a significant reduction of AT4/IRAP expression in diabetics renal tissues compared to non-diabetics (p=0.01). Conclusions: Recently AT4 (angiotensin IV receptor) was identified as IRAP (insulin regulated aminopeptidase). The AT4/IRAP was originally identified from GLUT4 vesicles and thought to be involved in insulin sensitivity. On the other hands, AT4/IRAP is thought to degrade angiotensin III to angiotensin IV and to further degraded fragments. Thus, the results suggest that reduction of IRAP/ AT4 in renal tissue might be involved in formation and progression of diabetic nephropathy.
Special Issue “Diabetic Nephropathy: Diagnosis, Prevention and Treatment”
Journal of Clinical Medicine, 2020
Diabetic nephropathy (DN) is the main cause of end-stage renal disease. DN is a complex disease mediated by genetic and environmental factors, and many cellular and molecular mechanisms are involved in renal damage in diabetes. There are no biomarkers that reflect the severity of the underlying renal histopathological changes and can effectively predict the progression of renal damage and stratify the risk of DN among individuals with diabetes mellitus. Current therapeutic strategies are based on the strict control of glucose and blood pressure levels and, although there are new anti-diabetic drugs, these treatments only retard renal damage progression, being necessary novel therapies. In this Special Issue, there are several comprehensive reviews and interesting original papers covering all these topics, which would be of interest to the growing number of readers of the Journal of Clinical Medicine.
Overview: Combating Diabetic Nephropathy
Journal of the American Society of Nephrology, 2003
Much has been said in the scientific and lay media about the growing epidemic of diabetes around the globe, but individuals and societies should never lose sight of the immeasurable human suffering and the enormous healthcare costs that this epidemic exacts. With the growing population of type 2 diabetes, the prevalence of diabetic nephropathy is on the rise, and there is an urgent need to define the pathophysiologic mechanisms for this devastating disorder. Genetic factors conspire with metabolic and hemodynamic insults to induce renal injury in susceptible individuals. In the current issue of the Journal of the American Society of Nephrology, four authoritative papers provide a balanced overview of the pathogenesis of the disease along with a comprehensive update on the clinical aspects and current management of diabetic nephropathy. Only by translating the new understanding of diabetic nephropathy into medical practice and implementing widespread clinical guidelines will we ever ensure that all at-risk patients receive the ideal care to stem the epidemic and stop nephropathy in its tracks.