Gene expression of the renin-angiotensin system in human kidney

Lai, Kar Neng; Leung, Jospeh C.K.; Lai, Ka Bik; To, Wah Yuen; Yeung, V. T. F.; Lai, Fernand Mac‐Moune

doi:10.1097/00004872-199816010-00014

Cited by 100 publications

(91 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gene and protein expression of angiotensinogen (Aogen), renin and ACE has been reported in cultured glomerular mesangial cells [12][13][14][15][16][17][18][19][20][21][22][23][24] and podocytes. [25][26][27][28] Mesangial expression of Aogen and ACE has also been documented in renal tissue sections.…”

Section: Intrarenal Raasmentioning

confidence: 99%

“…[25][26][27][28] Mesangial expression of Aogen and ACE has also been documented in renal tissue sections. 19,23 Mesangial cells synthesize Ang II 22,24 and aldosterone, the latter apparently through an Ang II-dependent mechanism. 29 Podocytes also produce Ang II 25,26,28 and aldosterone.…”

Section: Intrarenal Raasmentioning

confidence: 99%

“…29 Podocytes also produce Ang II 25,26,28 and aldosterone. 30 Angiotensin type 1 receptors are expressed on mesangial cells 19,24,31 and podocytes 26,28,32 and mineralocorticoid receptors are also expressed by both cell types. 29,33,34 The likely importance of the local glomerular RAAS relates to the pathogenesis of glomeruloscleorsis and the loss of glomerular permselectivity observed in many glomerular diseases.…”

Section: Intrarenal Raasmentioning

confidence: 99%

“…Renin mRNA and protein are expressed in the proximal and connecting tubules, as well as the collecting ducts. 19,[46][47][48][49][50][51][52][53][54] Interestingly, mechanisms for regulating tubular renin seem to be independent of those in the JG cell. 47,48,50,52 Proximal tubular cells express mRNA [54][55][56] and protein 53,57 for ACE and Aogen.…”

Section: Intrarenal Raasmentioning

confidence: 99%

See 3 more Smart Citations

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

View full text Add to dashboard Cite

The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

show abstract

Section: Intrarenal Raasmentioning

confidence: 99%

Section: Intrarenal Raasmentioning

confidence: 99%

Section: Intrarenal Raasmentioning

confidence: 99%

Section: Intrarenal Raasmentioning

confidence: 99%

See 2 more Smart Citations

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

View full text Add to dashboard Cite

show abstract

“…Angiotensin-II binds to several receptors augmenting both the inflammatory and fibrotic pathways, leading to the progression of disease. Increases in renal glomerular and tubular mRNA production of ACE, Atg and renin have been demonstrated in LN, 11 and pharmacological blockade of the RAS has consistently been shown to significantly decrease the progression of all proteinuric renal diseases. 12,13 Previously, using a family-based transmission-disequilibrium test (TDT) design in the same population, we found an association between ACE gene sequence variations and both SLE and LN among non-Caucasians.…”

Section: Introductionmentioning

confidence: 99%

Renin–angiotensin system gene polymorphisms predict the progression to renal insufficiency among Asians with lupus nephritis

et al. 2005

View full text Add to dashboard Cite

The renin-angiotensin system (RAS) is a strong candidate as a mediator for the development and progression of lupus nephritis (LN). We performed an ethnically stratified analysis of 642 systemic lupus erythematosus (SLE) patients to determine whether various functional RAS gene polymorphisms are associated with SLE renal outcomes. Patients were genotyped for two angiotensin-converting enzyme (ACE) gene polymorphisms: Alu insertion/deletion (I/D) and 23 949 (CT) 2/3 , and for two angiotensinogen (Atg) gene polymorphisms: M235T and C-532T. Multivariate analyses demonstrated associations between the ACE I/D, ACE (CT) 2/3 and Atg C-532T functional polymorphisms and LN among Asians. In stratified analyses among LN cases according to high vs low glomerular filtration rate (GFR), associations remained significant for the ACE D (odds ratio (OR) 5.9, P ¼ 0.001) and (CT) 2 (OR 6.2, P ¼ 0.001) alleles among Asian subjects with low GFR. Lastly, we found allelic dosedependent associations between the ACE I/D (P ¼ 0.003), ACE (CT) 2/3 (P ¼ 0.005) and Atg M235T (P ¼ 0.04) polymorphisms, and GFR analyzed as a continuous variable among Asians. These findings suggest a significant role for ACE and Atg gene sequence variation and severity of LN among Asians with SLE.

show abstract

Apoptosis of lung epithelial cells in response to TNF‐α requires angiotensin II generation de novo

Wang

Alam

Zagariya

et al. 2000

Journal Cellular Physiology

127

108

View full text Add to dashboard Cite

Recent work from this laboratory demonstrated that apoptosis of pulmonary alveolar epithelial cells (AEC) in response to Fas requires angiotensin II (ANGII) generation de novo and binding to its receptor (Wang et al., 1999b, Am J Physiol Lung Cell Mol Physiol 277:L1245-L1250). These findings led us to hypothesize that a similar mechanism might be involved in the induction of AEC apoptosis by TNF-alpha. Apoptosis was detected by assessment of nuclear and chromatin morphology, increased activity of caspase 3, binding of annexin V, and by net cell loss inhibitable by the caspase inhibitor ZVAD-fmk. Purified human TNF-alpha induced dose-dependent apoptosis in primary type II pneumocytes isolated from rats or in the AEC-derived human lung carcinoma cell line A549. Apoptosis in response to TNF-alpha was inhibited in a dose-dependent manner by the nonselective ANGII receptor antagonist saralasin or by the nonthiol ACE inhibitor lisinopril; the inhibition of TNF-induced apoptosis was maximal at 50 microgram/ml saralasin (101% inhibition) and at 0.5 microgram/ml lisinopril (86% inhibition). In both cell culture models, purified TNF-alpha caused a significant increase in the mRNA for angiotensinogen (ANGEN), which was not expressed in unactivated cells. Transfection of primary cultures of rat AEC with antisense oligonucleotides against ANGEN mRNA inhibited the subsequent induction of TNF-stimulated apoptosis by 72% (P < 0.01). Exposure to TNF-alpha increased the concentration of ANGII in the serum-free extracellular medium by fivefold in A549 cell cultures and by 40-fold in primary AEC preparations; further, exposure to TNF-alpha for 40 h caused a net cell loss of 70%, which was completely abrogated by either the caspase inhibitor ZVAD-fmk, lisinopril, or saralasin. Apoptosis in response to TNF-alpha was also completely inhibited by neutralizing antibodies specific for ANGII (P < 0.01), but isotype-matched nonimmune immunoglobulins had no significant effect. These data indicate that the induction of AEC apoptosis by TNF-alpha requires a functional renin/angiotensin system (RAS) in the target cell. They also suggest that therapeutic control of AEC apoptosis in response to TNF-alpha is feasible through pharmacologic manipulation of the local RAS.

show abstract

Gene expression of the renin-angiotensin system in human kidney

Cited by 100 publications

References 23 publications

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Renin–angiotensin system gene polymorphisms predict the progression to renal insufficiency among Asians with lupus nephritis

Apoptosis of lung epithelial cells in response to TNF‐α requires angiotensin II generation de novo

Contact Info

Product

Resources

About