Transforming growth factor-beta 1 stimulates angiotensinogen gene expression in kidney proximal tubular cells

The present study investigated whether transforming growth factor-beta 1 (TGF-β1) exerts an autocrine positive effect on angiotensinogen (ANG) gene expression in rat kidney proximal tubular cells, and delineates its underlying mechanism(s) of action. Rat immortalized renal proximal tubular cells (IRPTCs) and freshly isolated mouse renal proximal tubules were incubated in the absence or presence of active human TGF-β1. IRPTCs were also stably transfected with rat TGF-β1 or p53 tumor suppressor protein (p53) cDNA in sense (S) and antisense (AS) orientations. ANG mRNA and p53 protein expression were assessed by reverse transcription-polymerase chain reaction and Western blotting, respectively. Reactive oxygen species (ROS) generation was quantified by lucigenin assay. Active TGF-β1 evoked ROS generation and stimulated ANG mRNA and p53 protein expression, whereas a superoxide scavenger and inhibitors of nicotinamide adenine dinucleotide oxidase and p38 mitogen-activated protein kinase (p38 MAPK) abolished the TGF-β1 effect. Stable transfer of p53 cDNA (S) enhanced and p53 cDNA (AS) abolished the stimulatory effect of TGF-β1 on ANG mRNA expression in IRPTCs. Our results demonstrate that TGF-β1 stimulates ANG gene expression and its action is mediated, at least in part, via ROS generation, p38 MAPK activation, and p53 expression, suggesting that angiotensin II and TGF-β1 may form a positive feedback loop to enhance their respective gene expression, leading to renal injury

Antihypertensive effects of crude extracts from leaves of Echinodorus grandiflorus

The antihypertensive action of a crude ethanolic extract (EEEG) from leaves of Echinodorus grandiflorus (Alismataceae) was investigated in spontaneously hypertensive rats. The intraperitoneal injection of increasing doses of EEEG (300-1000 mg/kg) elicited dose-dependent reductions in mean arterial pressure (MAP) that were paralleled by reductions of cardiac output and systemic vascular resistance, reaching the maximum of 23 +/- 5%, 13 +/- 3% and 18 +/- 4%, respectively (n = 5, P < 0.05). Comparable reductions of MAP were obtained upon i.v. administration of EEEG (3-100 mg/kg), reaching the maximum decrease of 51 +/- 6% (n = 7; P < 0.001). The blockade of nitric oxide synthesis significantly reduced the hypotension induced by i.v. administration of EEEG. Moreover, the pre-treatment of the animals with a selective antagonist of cholinergic muscarinic receptors or of platelet-activating factor (PAF) receptors partially blunted the cardiovascular effects of EEEG. The i.v. pre-treatment with the selective B(2) bradykinin receptor antagonist HOE 140 or with indomethacin, an inhibitor of the enzyme cyclooxygenase, did not prevent the hypotensive effects induced by EEEG. Finally, the chronic oral treatment with EEEG presented a significant antihypertensive effect that was comparable to that of reference antihypertensive drugs currently used to treat arterial hypertension. It is concluded that EEEG elicits significant acute antihypertensive effects through the release of nitric oxide and the stimulation of cholinergic muscarinic and PAF receptors. Moreover, our results suggest that EEEG may be appropriate to chronic oral treatment of arterial hypertension.2022-01-0

RAS blockade decreases blood pressure and proteinuria in transgenic mice overexpressing rat angiotensinogen gene in the kidney

Angiotensinogen (ANG) is the sole substrate of the renin–angiotensin system (RAS). Clinical studies have shown that RAS activation may lead to hypertension, a major cardiovascular and renal risk factor. To delineate the underlying mechanisms of hypertension-induced nephropathy, we generated transgenic mice that overexpress rat ANG (rANG) in the kidney to establish whether intrarenal RAS activation alone can evoke hypertension and kidney damage and whether RAS blockade can reverse these effects. Transgenic mice overexpressing renal rANG were generated by employing the kidney-specific, androgen-regulated protein promoter linked to rANG cDNA. This promoter targets rANG cDNA to renal proximal tubules and responds to androgen stimulation. Transgenic mice displayed kidney-specific expression of rANG, significantly increased blood pressure (BP) and albuminuria in comparison to non-transgenic littermates. Administration of losartan (an angiotensin II (type 1)-receptor antagonist) or perindopril (an angiotensin-converting enzyme inhibitor) reversed these abnormalities in transgenic animals. Renal injury was evident on examination of the kidneys in transgenic mice, and attenuated by losartan and perindopril treatment. We conclude that the overproduction of ANG alone in the kidney induces an increase in systemic BP, proteinuria, and renal injury. RAS blockers prevent these abnormalities. These data support the role of the intrarenal RAS in the development of hypertension and renal injury

Catalase overexpression attenuates angiotensinogen expression and apoptosis in diabetic mice

Increased generation of reactive oxygen species (ROS) leads to oxidative stress in diabetes. Catalase is a highly conserved heme-containing protein that reduces hydrogen peroxide to water and oxygen and is an important factor decreasing cellular injury owing to oxidative stress. Hyperglycemic conditions increase oxidative stress and angiotensinogen gene expression. Angiotensinogen conversion to angiotensin II leads to a furtherance in oxidative stress through increased generation of reactive oxygen species. In this study, we utilized mice transgenically overexpressing rat catalase in a kidney-specific manner to determine the impact on ROS, angiotensinogen and apoptotic gene expression in proximal tubule cells of diabetic animals. Proximal tubules isolated from wild-type and transgenic animals without or with streptozotocin-induced diabetes were incubated in low glucose media in the absence or presence of angiotensin II or in a high-glucose media. Our results show that the overexpression of catalase prevents the stimulation of ROS and angiotensinogen mRNA in tubules owing to elevated glucose or angiotensin II in vitro. Additionally, overexpression of catalase attenuated ROS generation, angiotensinogen and proapoptotic gene expression and apoptosis in the kidneys of diabetic mice in vivo. Our studies point to an important role of ROS in the pathophysiology of diabetic nephropathy

The Atlas of Inflammation Resolution (AIR)

Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi- and interdisciplinary approach necessary. The Atlas of Inflammation Resolution (AIR) is a web-based resource capturing an essential part of the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. By mapping experimental data onto the AIR, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The AIR was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses. The AIR is accessible through https://air.bio.informatik.uni-rostock.de