Diabetic nephropathy: diagnosis and treatment Fineberg, Daniel; Jandeleit-Dahm, Karin A M; Cooper, Mark E
Nature reviews. Endocrinology,
12/2013, Letnik:
9, Številka:
12
Journal Article
Recenzirano
Nephropathy remains a major cause of morbidity and a key determinant of mortality in patients with type 1 or type 2 diabetes mellitus. Research is ongoing to identify biomarkers that in addition to ...albuminuria and glomerular filtration rate assist in the prediction and monitoring of renal disease in diabetes mellitus. Current strategies to treat this condition focus on intensification of glycaemic control and excellent control of blood pressure using regimens based on blockade of the renin-angiotensin system. Other approaches to control blood pressure and afford renoprotection are under active clinical investigation, including renal denervation and endothelin receptor antagonism. With increasing understanding of the underlying pathophysiological processes implicated in diabetic nephropathy, new specific renoprotective treatment strategies are anticipated to become available over the next few years.
Aims/hypothesis
Oxidative stress is a promising target in diabetes-associated vasculopathies, with inhibitors of NADPH oxidases (NOX), in particular isoforms 1 and 4, shown to be safe in early ...clinical development. We have explored a highly relevant late-stage intervention protocol using the clinically most advanced compound, the NOX1/4 inhibitor GKT137831, to determine whether end-organ damage can be reversed/attenuated when GKT137831 is administered in the setting of established diabetic complications.
Methods
GKT137831 was administered at two doses, 30 mg kg
−1
day
−1
and 60 mg kg
−1
day
−1
, to
ApoE
−/−
mice 10 weeks after diabetes induction with streptozotocin (STZ), for a period of 10 weeks.
Results
Consistent with
Nox4
−/−
mouse data, GKT137831 was protective in a model of diabetic nephropathy at both the 30 mg kg
−1
day
−1
and 60 mg kg
−1
day
−1
doses, through suppression of proinflammatory and profibrotic processes. Conversely, in diabetic atherosclerosis, where
Nox1
−
/y
and
Nox4
−
/−
mice have yielded qualitatively opposing results, the net effect of pharmacological NOX1/4 inhibition was protection, albeit to a lower extent and only at the lower 30 mg kg
−1
day
−1
dose.
Conclusions/interpretation
As dose-dependent and tissue-specific effects of the dual NOX1/4 inhibitor GKT137831 were observed, it is critical to define in further studies the relative balance of inhibiting NOX4 vs NOX1 in the micro- and macrovasculature in diabetes.
The kidney is arguably the most important target of microvascular damage in diabetes. A substantial proportion of individuals with diabetes will develop kidney disease owing to their disease and/or ...other co-morbidity, including hypertension and ageing-related nephron loss. The presence and severity of chronic kidney disease (CKD) identify individuals who are at increased risk of adverse health outcomes and premature mortality. Consequently, preventing and managing CKD in patients with diabetes is now a key aim of their overall management. Intensive management of patients with diabetes includes controlling blood glucose levels and blood pressure as well as blockade of the renin-angiotensin-aldosterone system; these approaches will reduce the incidence of diabetic kidney disease and slow its progression. Indeed, the major decline in the incidence of diabetic kidney disease (DKD) over the past 30 years and improved patient prognosis are largely attributable to improved diabetes care. However, there remains an unmet need for innovative treatment strategies to prevent, arrest, treat and reverse DKD. In this Primer, we summarize what is now known about the molecular pathogenesis of CKD in patients with diabetes and the key pathways and targets implicated in its progression. In addition, we discuss the current evidence for the prevention and management of DKD as well as the many controversies. Finally, we explore the opportunities to develop new interventions through urgently needed investment in dedicated and focused research. For an illustrated summary of this Primer, visit: http://go.nature.com/NKHDzg.
RAGE biology, atherosclerosis and diabetes Barlovic, Drazenka Pongrac; Soro-Paavonen, Aino; Jandeleit-Dahm, Karin A M
Clinical science (1979),
07/2011, Letnik:
121, Številka:
2
Journal Article
Recenzirano
Diabetes is characterized by accelerated atherosclerosis with widely distributed vascular lesions. An important mechanism by which hyperglycaemia contributes to vascular injury is through the ...extensive intracellular and extracellular formation of AGEs (advanced glycation end products). AGEs represent a heterogeneous group of proteins, lipids and nucleic acids, irreversibly cross-linked with reducing sugars. AGEs are implicated in the atherosclerotic process, either directly or via receptor-mediated mechanisms, the most extensively studied receptor being RAGE (receptor for AGEs). The AGE-RAGE interaction alters cellular signalling, promotes gene expression and enhances the release of pro-inflammatory molecules. It elicits the generation of oxidative stress in numerous cell types. The importance of the AGE-RAGE interaction and downstream pathways leading to injurious effects as a result of chronic hyperglycaemia in the development, progression and instability of diabetic atherosclerotic lesions has been amply demonstrated in animal studies. Moreover, the deleterious link of AGEs with diabetic vascular complications has been suggested in many human studies. In the present review, our current understanding of their role as an important mediator of vascular injury through the various stages of atherosclerosis in diabetes will be reviewed and critically assessed.
The let-7 miRNA family plays a key role in modulating inflammatory responses. Vascular smooth muscle cell (SMC) proliferation and endothelial cell (EC) dysfunction are critical in the pathogenesis of ...atherosclerosis, including in the setting of diabetes. Here we report that let-7 levels are decreased in diabetic human carotid plaques and in a model of diabetes-associated atherosclerosis, the diabetic ApoE
mouse. In vitro platelet-derived growth factor (PDGF)- and tumor necrosis factor-α (TNF-α)-induced vascular SMC and EC activation was associated with reduced let-7 miRNA expression via Lin28b, a negative regulator of let-7 biogenesis. Ectopic overexpression of let-7 in SMCs inhibited inflammatory responses including proliferation, migration, monocyte adhesion, and nuclear factor-κB activation. The therapeutic potential of restoring let-7 levels using a let-7 mimic was tested: in vitro in SMCs using an endogenous anti-inflammatory lipid (lipoxin A
), ex vivo in murine aortas, and in vivo via tail vein injection in a 24-h murine model. Furthermore, we delivered let-7 mimic to human carotid plaque ex vivo and observed significant changes to the secretome in response to let-7 therapy. Restoration of let-7 expression could provide a new target for an anti-inflammatory approach in diabetic vascular disease.
Oxidative stress is considered a hallmark of atherosclerosis. In particular, the superoxide-generating type 1 NADPH oxidase (NOX1) has been shown to be induced and play a pivotal role in early phases ...of mouse models of atherosclerosis and in the context of diabetes mellitus. Here, we investigated the role of the most abundant type 4 isoform (NOX4) in human and mouse advanced atherosclerosis.
Plaques of patients with cardiovascular events or established diabetes mellitus showed a surprising reduction in expression of the most abundant but hydrogen peroxide (H2O2)-generating type 4 isoform (Nox4), whereas Nox1 mRNA was elevated, when compared with respective controls. As these data suggested that NOX4-derived reactive oxygen species may convey a surprisingly protective effect during plaque progression, we examined a mouse model of accelerated and advanced diabetic atherosclerosis, the streptozotocin-treated ApoE(-/-) mouse, with (NOX4(-/-)) and without genetic deletion of Nox4. Similar to the human data, advanced versus early plaques of wild-type mice showed reduced Nox4 mRNA expression. Consistent with a rather protective role of NOX4-derived reactive oxygen species, NOX4(-/-) mice showed increased atherosclerosis when compared with wild-type mice. Deleting NOX4 was associated with reduced H2O2 forming activity and attenuation of the proinflammatory markers, monocyte chemotratic protein-1, interleukin-1β, and tumor necrosis factor-α, as well as vascular macrophage accumulation. Furthermore, there was a greater accumulation of fibrillar collagen fibres within the vascular wall and plaque in diabetic Nox4(-/-)ApoE(-/-) mice, indicative of plaque remodeling. These data could be replicated in human aortic endothelial cells in vitro, where Nox4 overexpression increased H2O2 and reduced the expression of pro-oxidants and profibrotic markers. Interestingly, Nox4 levels inversely correlated with Nox2 gene and protein levels. Although NOX2 is not constitutively active unlike NOX4 and forms rather superoxide, this opens up the possibility that at least some effects of NOX4 deletion are mediated by NOX2 activation.
Thus, the appearance of reactive oxygen species in atherosclerosis is apparently not always a nondesirable oxidative stress, but can also have protective effects. Both in humans and in mouse, the H2O2-forming NOX4, unlike the superoxide-forming NOX1, can act as a negative modulator of inflammation and remodeling and convey atheroprotection. These results have implications on how to judge reactive oxygen species formation in cardiovascular disease and need to be considered in the development of NOX inhibitory drugs.
Oxidative stress and inflammation are considered major drivers in the pathogenesis of diabetic complications, including renal and cardiovascular disease. A symbiotic relationship also appears to ...exist between oxidative stress and inflammation. Several emerging therapies target these crucial pathways, to alleviate the burden of the aforementioned diseases. Oxidative stress refers to an imbalance between reactive oxygen species (ROS) and antioxidant defenses, a pathological state which not only leads to direct cellular damage but also an inflammatory cascade that further perpetuates tissue injury. Emerging therapeutic strategies tackle these pathways in a variety of ways, from increasing antioxidant defenses (antioxidants and Nrf2 activators) to reducing ROS production (NADPH oxidase inhibitors and XO inhibitors) or inhibiting the associated inflammatory pathways (NLRP3 inflammasome inhibitors, lipoxins, GLP-1 receptor agonists, and AT-1 receptor antagonists). This review summarizes the mechanisms by which oxidative stress and inflammation contribute to and perpetuate diabetes associated renal and cardiovascular disease along with the therapeutic strategies which target these pathways to provide reno and cardiovascular protection in the setting of diabetes.
Atherosclerosis is a disease of large and medium arteries that can lead to life-threatening cerebrovascular and cardiovascular consequences such as heart failure and stroke and is a major contributor ...to cardiovascular-related mortality worldwide. Atherosclerosis development is a complex process that involves specific structural, functional and transcriptional changes in different vascular cell populations at different stages of the disease. The application of single-cell RNA sequencing (scRNA-seq) analysis has discovered not only disease-related cell-specific transcriptomic profiles but also novel subpopulations of cells once thought as homogenous cell populations. Vascular cells undergo specific transcriptional changes during the entire course of the disease. Epigenetics is the instruction-set-architecture in living cells that defines and maintains the cellular identity by regulating the cellular transcriptome. Although different cells contain the same genetic material, they have different epigenomic signatures. The epigenome is plastic, dynamic and highly responsive to environmental stimuli. Modifications to the epigenome are driven by an array of epigenetic enzymes generally referred to as writers, erasers and readers that define cellular fate and destiny. The reversibility of these modifications raises hope for finding novel therapeutic targets for modifiable pathological conditions including atherosclerosis where the involvement of epigenetics is increasingly appreciated. This article provides a critical review of the up-to-date research in the field of epigenetics mainly focusing on in vivo settings in the context of the cellular role of individual vascular cell types in the development of atherosclerosis.
Aims/hypothesis
We determined whether empagliflozin altered renal sympathetic nerve activity (RSNA) and baroreflexes in a diabetes model in conscious rabbits.
Methods
Diabetes was induced by alloxan, ...and RSNA, mean arterial pressure (MAP) and heart rate were measured before and after 1 week of treatment with empagliflozin, insulin, the diuretic acetazolamide or the ACE inhibitor perindopril, or no treatment, in conscious rabbits.
Results
Four weeks after alloxan administration, blood glucose was threefold and MAP 9% higher than non-diabetic controls (
p
< 0.05). One week of treatment with empagliflozin produced a stable fall in blood glucose (−43%) and increased water intake (+49%) but did not change RSNA, MAP or heart rate compared with untreated diabetic rabbits. The maximum RSNA to hypotension was augmented by 75% (
p
< 0.01) in diabetic rabbits but the heart rate baroreflex was unaltered. Empagliflozin and acetazolamide reduced the augmentation of the RSNA baroreflex (
p
< 0.05) to be similar to the non-diabetic group. Noradrenaline (norepinephrine) spillover was similar in untreated diabetic and non-diabetic rabbits but twofold greater in empagliflozin- and acetazolamide-treated rabbits (
p
< 0.05).
Conclusions/interpretation
As empagliflozin can restore diabetes-induced augmented sympathetic reflexes, this may be beneficial in diabetic patients. A similar action of the diuretic acetazolamide suggests that the mechanism may involve increased sodium and water excretion.
Graphical abstract
Abstract
Atherosclerosis and its complications are major causes of cardiovascular morbidity and death. Apart from risk factors such as hypercholesterolemia and inflammation, the causal molecular ...mechanisms are unknown. One proposed causal mechanism involves elevated levels of reactive oxygen species (ROS). Indeed, early expression of the ROS forming NADPH oxidase type 5 (
Nox5
) in vascular endothelial cells correlates with atherosclerosis and aortic aneurysm. Here we test the pro-atherogenic
Nox5
hypothesis using mouse models. Because
Nox5
is missing from the mouse genome, a knock-in mouse model expressing human
Nox5
in its physiological location of endothelial cells (eNOX5
ki/ki
) was tested as a possible new humanised mouse atherosclerosis model. However, whether just on a high cholesterol diet or by crossing in aortic atherosclerosis-prone
ApoE
−/−
mice with and without induction of diabetes, Nox5 neither induced on its own nor aggravated aortic atherosclerosis. Surprisingly, however, diabetic ApoE
−/−
x eNOX5
ki/ki
mice developed aortic aneurysms more than twice as often correlating with lower vascular collagens, as assessed by trichrome staining, without changes in inflammatory gene expression, suggesting that endothelial Nox5 directly affects extracellular matrix remodelling associated with aneurysm formation in diabetes. Thus
Nox5
-derived reactive oxygen species are not a new independent mechanism of atherosclerosis but may enhance the frequency of abdominal aortic aneurysms in the context of diabetes. Together with similar clinical findings, our preclinical target validation opens up a first-in-class mechanism-based approach to treat or even prevent abdominal aortic aneurysms.
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