N -Acetyl-Seryl-Aspartyl-Lysyl-Proline Attenuates Renal Injury and Dysfunction in Hypertensive Rats With Reduced Renal Mass

Disruption of Smad4 impairs TGF-β/Smad3 and Smad7 transcriptional regulation during renal inflammation and fibrosis in vivo and in vitro

Reactive oxygen species (ROS) produced in the neuronal, renal, and vascular systems not only influence cardiovascular physiology but are also strongly implicated in pathological signaling leading to hypertension. Different sources of ROS have been identified, ranging from xanthine-xanthine oxidase and mitochondria to NADPH oxidase (Nox) enzymes. Of 7 Nox family members, Nox1, Nox2, and Nox4 (and Nox5 in humans) influence the cardiovascular system. Their activation processes and cell and tissue distribution vary widely, adding complexity to understanding their functional roles. Whether these systems act collectively or independently in disease conditions is unclear, but recently feed forward mechanisms have been established between ROS sources. Studies published in Hypertension over the last few years are the focus of this review, and they provide a framework with which to consider the roles of Nox enzymes in neuronal, renal, and vascular hypertensive mechanisms, as well as cardiac remodeling, and their relationships with other ROS-generating systems. ### Neuronal ROS in Hypertension Redox signaling in the central nervous system is well recognized in neuronal control of blood pressure (BP), as well as in response to angiotensin II (Ang II) and aldosterone, which are linked to ROS-dependent hypertension. Recently, new roles for ROS have been described in the hypothalamus and brain stem, nucleus tractus solitarius (NTS), subfornical organ (SFO), rostral ventrolateral medulla, and area postrema (Figure 1). Figure 1. Neuronal NADPH oxidase–dependent ROS involved in central regulation of hypertension. NADPH oxidase homologues, mainly Nox2 and Nox4, are found in different regions of the neuronal system and are reported to have a role in the neuropathogenesis of hypertension by enhancing the sympathetic nerve activity. Nox-induced ROS initiate a forward loop in cross-activation of different receptors and between Nox and mitochondrial ROS. OVLT indicates organum vasculosum of the lamina terminalis; PVN, paraventricular nucleus; PP, posterior pituitary; AP, area postrema; RVLM, rostral ventrolateral medulla. Several …

Plasminogen activator inhibitor-1 deficiency protects against aldosterone-induced glomerular injury

Mitochondria were first described in 1840 as bioblasts, elementary organisms responsible for vital cellular functions, but were subsequently named mitochondria, from the Greek names mitos (thread) and chondros (granule), which describes their appearance during spermatogenesis.1 Their discovery generated substantial interest given their structure resembling bacteria, which led in subsequent years to important scientific discoveries positioning mitochondria as the energy powerhouse of the cell. The unique architecture of mitochondria, consisting of 2 membranes (outer and inner) and compartments (intermembrane space and matrix), is crucial for their vital functions. Mitochondria serve not only as primary sources of cellular energy, but also modulate several cellular processes, including oxidative phosphorylation, calcium homeostasis, thermogenesis, oxygen sensing, proliferation, and apoptosis.2 Therefore, mitochondrial injury and dysfunction might be implicated in the pathogenesis of several diseases. Hypertension accounts for nearly 30% of patients reaching end-stage renal disease.3 Renal injury secondary to hypertension or to ischemia associated with renovascular hypertension (distal to renal artery stenosis) may have significant and detrimental effect on health outcomes. Studies have highlighted several deleterious pathways, including inflammation, oxidative stress, and fibrosis that are activated in the hypertensive kidney, eliciting functional decline.4,5 However, the precise molecular mechanisms responsible for renal injury have not been fully elucidated. Over the past few years, increasing evidence has established the experimental foundations linking mitochondrial alterations to hypertensive renal injury (Table). Mitochondriopathies, abnormalities of energy metabolism secondary to sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA) genes, may contribute to the development and progression of hypertension and its complications. In addition, several studies have reported mitochondrial damage and dysfunction consequent to hypertensive renal disease. View this table: Table. Evidence of Renal Mitochondrial Damage in Models of Hypertension and Antihypertensive Treatment Importantly, hypertensive-induced renal injury is characterized by activation of several deleterious pathways, including oxidative stress, renin–angiotensin–aldosterone …

R enin angiotensin system (RAS) antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists are increasingly used to treat cardiovascular and other diseases (1–6). These treatments induce a blockade of the RAS that may affect hemodynamics during anesthesia and surgery. In 1978, Miller et al. (7) reported that the RAS is involved in maintaining normal blood pressure during anesthesia. Although anesthesia is not invariably associated with a deleterious hemodynamic event in RAS-blocked patients (8–10), hemodynamic instability, described as unexpected episodes of hypotension, have been reported (11–13). Otherwise, stresses such as surgery or hypotension stimulate the generation of angiotensin II, which induces vasoconstriction (14) to maintain blood pressure but reduces blood flow to organs such as the kidneys and bowels. Accordingly, an angiotensin II-induced reduction in blood flow may contribute to acute renal failure (15) and splanchnic ischemia (16), which are obvious factors in postoperative morbidity (17). RAS blockade with ACE inhibitors decreases some consequences of the stress response on the regional circulation (9,18,19), which may then contribute to body protection. Much of the information regarding the physiology and pathophysiology of the RAS during anesthesia and surgery is based on the effects of ACE inhibitors. Because ACE inhibitors probably act mostly by blocking the RAS, similar effects should be obtained from angiotensin (AT) receptor antagonists. RAS antagonist pharmacology may help us to understand the hemodynamic risk of anesthesia in RAS-blocked patients, to identify predisposing factors, and to determine the potential benefit of RAS antagonists during anesthesia and surgery. Physiology of the RAS Generation of Angiotensin II

Left Ventricular Hypertrophy in Mild and Moderate Reduction in Kidney Function Determined Using Cardiac Magnetic Resonance Imaging and Cystatin C: The Multi-Ethnic Study of Atherosclerosis (MESA)

Cardiac hypertrophy is a morphological adaptive increase in myocardial mass in response to chronic work overload and is a common clinical finding affecting 23% of men and 33% of women over the age of 59 years [1]. Pressure or volume overload on the myocardium results in an increase in myocardial wall stress and hypertrophy may be seen as an attempt to normalise wall stress and oxygen demand. Although initially protective, the increased myocardial mass requires an increase in coronary blood flow to maintain function; indeed, ventricular hypertrophy may be associated with myocardial ischaemia even with angiographically normal coronary arteries [2–4]. Left ventricular hypertrophy (LVH) significantly increases the risk of myocardial infarction, congestive heart failure and sudden cardiac death [5–7]. It is also associated with a greater prevalence of cardiac arrhythmias [8] and is an important risk factor for cardiac morbidity and mortality [9–10]. Understanding the potential mechanisms for these adverse effects has been the focus of much interest in recent years.

Background: Vasopressin (AVP) type 1a receptor (V1aR) antagonist could theoretically benefit heart failure (HF) patients by decreasing afterload and ameliorating remodeling. However, the conflicting results have been reported. Also, there is a concern that increased AVP may have detrimental effects through V1aR in HF patients treated with oral type 2 receptor (V2R) antagonist, tolvaptan. Therefore, we examined whether the chronic administration of V1a antagonist may exert beneficial effects and also its additive effects to tolvaptan treatment in rat hypertensive HF model. Methods and results: In Dahl salt-sensitive hypertensive rats, not only circulating AVP level, but also myocardial AVP and V1a receptor (V1aR), and renal V1aR and V2R expressions were significantly activated during the transition to HF (18-21 weeks). First, they were chronically treated with vehicle, V1aR antagonist (OPC21268), tolvaptan, or OPC21268 plus tolvaptan (combination) from pre-hypertrophic stage (6 weeks). All three treatments did not affect blood pressure. In OPC21268 and tolvaptan groups, the median survival time was significantly improved from 112 day (vehicle) to 141 day and 160 day, respectively. It was improved to a greater extent with the combined treatment (175 day). Echocardiography showed the improvement of fractional shortening (FS) was observed in all three treatment groups and the suppression of LV hypertrophy (LVH) only in OPC 21268 and combination groups. Furthermore, renal histopathologic damage (glomerulosclerosis and tubulointerstitial fibrosis) was ameliorated, and renal function (creatinine clearance) was also improved in all three treatment groups at HF stage. When these treatments were started at the established LVH phase (11 weeks), the improvement of survival was observed only in tolvaptan group and no additive improvement in the combined treatment. Conclusions: These findings suggest that V1aR blockade may ameliorate the development of LVH and HF in the treatment of hypertensive HF with renal injuries, and have limited effects starting after the establishment of LVH. Also, the chronic administration of both V1a and V2 antagonists exerts further beneficial effects. The underlying mechanism may be related to protection of myocardial and renal damages independent of blood pressure.

Ramipril

Cardiorenal syndrome: pathophysiology, role of protein-bound uraemic toxins

Complications of Progression of CKD

Renal fibrosis, the final pathway of chronic kidney disease, is caused by genetic and epigenetic mechanisms. Although DNA methylation has drawn attention as a developing mechanism of renal fibrosis, its contribution to renal fibrosis has not been clarified. To address this issue, the effect of zebularine, a DNA methyltransferase inhibitor, on renal inflammation and fibrosis in the murine unilateral ureteral obstruction (UUO) model was analyzed. Zebularine significantly attenuated renal tubulointerstitial fibrosis and inflammation. Zebularine decreased trichrome, α-smooth muscle actin, collagen IV, and transforming growth factor-β1 staining by 56.2%. 21.3%, 30.3%, and 29.9%, respectively, at 3 days, and by 54.6%, 41.9%, 45.9%, and 61.7%, respectively, at 7 days after UUO. Zebularine downregulated mRNA expression levels of matrix metalloproteinase (MMP)-2, MMP-9, fibronectin, and Snail1 by 48.6%. 71.4%, 31.8%, and 42.4%, respectively, at 7 days after UUO. Zebularine also suppressed the activation of nuclear factor-κB (NF-κB) and the expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, by 69.8%, 74.9%, and 69.6%, respectively, in obstructed kidneys. Furthermore, inhibiting DNA methyltransferase buttressed the nuclear expression of nuclear factor (erythroid-derived 2)-like factor 2, which upregulated downstream effectors such as catalase (1.838-fold increase at 7 days, p < 0.01), superoxide dismutase 1 (1.494-fold increase at 7 days, p < 0.05), and NAD(P)H: quinone oxidoreduate-1 (1.376-fold increase at 7 days, p < 0.05) in obstructed kidneys. Collectively, these findings suggest that inhibiting DNA methylation restores the disrupted balance between pro-inflammatory and anti-inflammatory pathways to alleviate renal inflammation and fibrosis. Therefore, these results highlight the possibility of DNA methyltransferases as therapeutic targets for treating renal inflammation and fibrosis.

Interferon regulatory factor 4 a master regulator of hypertensive kidney fibrosis and inflammation?

Introduction and Aims: Elevated plasma levels of C-reactive protein (CRP) are closely associated with progressive renal injury in patients with chronic kidney disease (CKD). Here, we tested a hypothesis that CRP may promote renal fibrosis and inflammation via a TGF-β/Smad3-dependent mechanism.Methods: Role and mechanisms of TGF-β/Smad3 in CRP-induced renal fibrosis and inflammation were examined in a mouse model of unilateral ureteral obstruction (UUO) induced in CRP Tg/Smad3 KO mice and in a rat tubular epithelial cell line in which Smad3 gene is stably knocked down (S3KD-NRK52E).Results: We found that mice overexpressing the human CRP gene were largely promoted renal inflammation and fibrosis as evidenced by increasing IL-1β, TNF-α, MCP-1 expression, F4/80+ macrophages infiltration, and marked accumulation of α-smooth muscle actin (α-SMA), collagen I and fibronectin in the UUO kidney, which were blunted when Smad3 gene was deleted in CRPtg-Smad3KO. Mechanistically, we found that the protection of renal inflammation and fibrosis in the UUO kidney of CRPtg-Smad3KO mice was associated with the inactivation of CD32-NF-κB and TGF-β/Smad3 signaling.Conclusion: In conclusion, Smad3 deficiency protects against CRP-mediated renal inflammation and fibrosis in the UUO kidney by inactivating CD32-NF-κB and TGF-β/Smad3 signaling.

The Selective A3AR Antagonist LJ-1888 Ameliorates UUO-Induced Tubulointerstitial Fibrosis