Diabetic nephropathy is a significant cause of chronic kidney disease and end-stage renal failure globally Much research has been conducted in both basic science and clinical therapeutics, which has enhanced understanding of the pathophysiology of diabetic nephropathy and expanded the potential therapies available This review will examine the current concepts of diabetic nephropathy management in the context of some of the basic science and pathophysiology aspects relevant to the approaches taken in novel, investigative treatment strategies

/pdf/diabetic-nephropathy-complications-and-treatment-arovwpix56.pdf

Diabetic nephropathy - complications and treatment.

The classical concept of the renin–angiotensin system (RAS) is that of a blood-borne cascade, whose final and bioactive product, angiotensin II, plays an important endocrine role in the maintenance of blood pressure and electrolyte as well as fluid balance. In addition to this circulating RAS, there are an increasing number of studies to suggest the existence of a local angiotensin-generating system in several tissues. The so-called tissue RAS can act locally as a paracrine and/or autocrine factor in meeting specific needs for individual tissues and it can operate, in whole or in part, independently of the circulating counterpart. Recent studies on the expression and localization of key RAS components, particularly angiotensinogen and renin, have provided solid evidence for the existence of an intrinsic, angiotensin-generating system in the pancreas. The tissue RAS has a potential role in finely regulating exocrine and endocrine functions of the pancreas such as ductal anion secretion and islet hormonal secretion. Some of these effects may be exerted via the markedly vasoconstrictive effects of RAS. Of particular interest in this context are the recent epidemiological data showing that administration of angiotensin-converting enzyme inhibitors appears to be protective against the development of diabetes in hypertensive patients. Moreover, the upregulation of pancreatic RAS has been shown to occur during chronic hypoxia. The significance of changes in pancreatic RAS could have a potential role in acute pancreatitis, islet transplantation and in different shock states, by causing a further decrease of blood perfusion in the pancreas.

/pdf/tissue-renin-angiotensin-system-its-expression-localization-ymi3q81gia.pdf

Tissue renin-angiotensin system: its expression, localization, regulation and potential role in the pancreas

Several regulatory systems are implicated in the regulation of islet function and beta cell mass. Of great interest in this context are some endocrine, paracrine/autocrine, and intracrine regulators. These include, to name but a few, the gut peptides, growth factors, prostaglandins, and some vasoactive mediators such as nitric oxide, bradykinins, endothelins, and angiotensins. Apart from its potent vasoconstrictor actions, the renin-angiotensin system (RAS) that generates angiotensin II has several novel functions-stimulation and inhibition of cell proliferation; induction of apoptosis; generation of reactive oxygen species; regulation of hormone secretion; and proinflammatory and profibrogenic actions. In the pancreas, recent evidence supports the presence of an islet RAS, which is subject to activation by islet transplantation and diabetes. Such a local islet RAS, if activated, may drive islet fibrosis and reduce islet blood flow, oxygen tension, and insulin biosynthesis. Moreover, activation of an islet RAS may drive the synthesis of reactive oxygen species, cause oxidative stress-induced beta cell dysfunction and apoptosis, and thus contribute to the islet dysfunction seen in type 2 diabetes and after islet transplantation. Blockade of the RAS could contribute to the development of novel therapeutic strategies in the prevention and treatment of patients with diabetes and in islet transplantation.

Pancreatic islet renin angiotensin system: its novel roles in islet function and in diabetes mellitus.

Aging is associated with an imbalance in sympathetic and parasympathetic outflow to cardiovascular effector organs. This autonomic imbalance contributes to the decline in cardiovagal baroreceptor reflex function during aging, which allows for unrestrained activation of the sympathetic nervous system to negatively impact resting systolic blood pressure and its variability. Further, impaired baroreflex function can contribute to the development of insulin resistance and other features of the metabolic syndrome during aging through overlap in autonomic neural pathways that regulate both cardiovascular and metabolic functions. Increasing evidence supports a widespread influence of the renin-angiotensin system (RAS) on both sympathetic and parasympathetic activity through receptors distributed to peripheral and central sites of action. Indeed, therapeutic interventions to block the RAS are well established for the treatment of hypertension in elderly patients, and reduce the incidence of new-onset diabetes in clinical trials. Further, RAS blockade increases lifespan and improves numerous age-related pathologies in rodents, often independent of blood pressure. The beneficial effects of these interventions are at least in part attributed to suppression of angiotensin II formed locally within the brain. In particular, recent insights from transgenic rodents provide evidence that long-term alteration in the brain RAS modulates the balance between angiotensin II and angiotensin-(1-7), and related intracellular signaling pathways, to influence cardiovascular and metabolic function in the context of hypertension and aging.

/pdf/brain-renin-angiotensin-system-in-the-nexus-of-hypertension-evx4nzr15o.pdf

Brain renin-angiotensin system in the nexus of hypertension and aging

Pathological activation of the renin-angiotensin system (RAS) is associated with the metabolic syndrome, and the new onset of type 2 diabetes can be delayed by RAS inhibition. In animal models of type 2 diabetes, inhibition of the RAS improves insulin secretion. However, the direct effects of angiotensin II on islet function and underlying mechanisms independent of changes in blood pressure remain unclear. Here we show that exposure of human and mouse islets to angiotensin II induces interleukin (IL)-1-dependent expression of IL-6 and MCP-1, enhances β-cell apoptosis, and impairs mitochondrial function and insulin secretion. In vivo, mice fed a high-fat diet and treated with angiotensin II and the vasodilator hydralazine to prevent hypertension showed defective glucose-stimulated insulin secretion and deteriorated glucose tolerance. Application of an anti-IL-1β antibody reduced the deleterious effects of angiotensin II on islet inflammation, restored insulin secretion, and improved glycemia. We conclude that angiotensin II leads to islet dysfunction via induction of inflammation and independent of vasoconstriction. Our findings reveal a novel role for the RAS and an additional rationale for the treatment of type 2 diabetic patients with an IL-1β antagonist.

https://diabetes.diabetesjournals.org/content/diabetes/64/4/1273.full.pdf

Angiotensin II induces interleukin-1β-mediated islet inflammation and β-cell dysfunction independently of vasoconstrictive effects.

E7: Angiotensin II affects basal, pulsatile and glucose-stimulated insulin secretion in humans

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E7: Angiotensin II affects basal, pulsatile and glucose-stimulated insulin secretion in humans