Renal ACE immunohistochemical localization in NIDDM patients with nephropathy

Mizuiri, Sonoo; Yoshikawa, Hiroko; Tanegashima, Masateru; Miyagi, Moriatsu; Kobayashi, M; Sakai, Ken; Hayashi, Izumi; Aikawa, Atsushi; Ohara, Takahiro; Hasegawa, Akira

doi:10.1053/ajkd.1998.v31.pm9469501

Cited by 54 publications

(26 citation statements)

References 16 publications

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“…With regard to ACE, the immunostain was elevated in tubular cells and appeared in interstitial cells (29). Another immunohistochemical study indicated that ACE staining was significantly enhanced in glomeruli in diabetic patients (30). The former study also reported a downregulation of AT1 and upregulation of AT2 receptors (29).…”

Section: Tissue Ras In Human Diabetic Nephropathymentioning

confidence: 89%

Tissue Gene Expression of Renin-Angiotensin System in Human Type 2 Diabetic Nephropathy

et al. 2006

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OBJECTIVE -Recent studies have proved that blockade of the renin-angiotensin system (RAS) retards the progression of diabetic nephropathy, whereas hyporeninemia is known as a typical state in diabetic subjects. The purpose of this study is to determine whether expression levels of RAS differ between nondiabetic and diabetic renal tissues with accurate quantitative method.RESEARCH DESIGN AND METHODS -Subjects were 66 nondiabetic and 8 diabetic patients with biopsy-proven renal diseases. The eight diabetic subjects suffered from type 2 diabetes with overt proteinuria. Renal histology revealed typical diffuse or nodular lesions with linear IgG deposit on immunofluorescent staining and thickened basement membrane on electronic microscopy. Total RNA from a small part of the renal cortical biopsy specimens was reverse-transcribed, and the resultant cDNA was amplified for new major components of RAS (i.e., renin, renin receptor, angiotensinogen, ACE, ACE2, angiotensin II type 1 receptor, and angiotensin II type 2 receptor) and measured.RESULTS -Among these components, a significant upregulation was observed in the ACE gene in diabetic renal tissue.CONCLUSIONS -The results suggest that renal tissue RAS might be activated in the respect that ACE gene expression is upregulated in spite of a tendency to low renin expression in type 2 diabetic nephropathy. Diabetes Care 29:848 -852, 2006R ecently proposed mechanisms for the development of diabetic nephropathy include glomerular hyperfiltration (1), disorientation of intracellular signal transduction (2), and involvement of advanced glycation end products (3). Activation of the reninangiotensin system (RAS) by high glucose, mechanical stress, and proteinuria has been implicated in the major changes associated with diabetic nephropathy (4). Thus, renal tissue activation of RAS is thought to contribute to deterioration in renal function of diabetic nephropathy. Recently, a number of large-scale prospective studies have proven that blockade of the system with ACE inhibitors and angiotensin II receptor blockers (ARBs) retards the progression of diabetic nephropathy (5-11). Actually, several studies suggest that the RAS is activated especially at the early stage (12,13). However, from early studies, hyporeninemia has been well known as a typical state of circulatory RAS in diabetic subjects at the late stage (14,15). Although the tissue RAS is thought to be controlled independently of the circulatory RAS, this apparent paradox is still difficult to interpret. It is supposed that the tissue RAS is activated in contrast to the circulatory RAS, and several non-or semiquantitative evaluations were made. However, direct or quantitative evidence in human diabetic nephropathy is very scarce so far. Furthermore, new major components for RAS, renin receptor (RER) (16), and ACE2 (17) have emerged recently.The purpose of this study is to determine whether expression levels of RAS including RER and ACE2 differ between nondiabetic and diabetic human renal tissues with full quantitative evalua...

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Section: Tissue Ras In Human Diabetic Nephropathymentioning

confidence: 89%

Tissue Gene Expression of Renin-Angiotensin System in Human Type 2 Diabetic Nephropathy

et al. 2006

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“…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. [58][59][60][61] In vivo evidence that proximal tubular cells may synthesize Ang II has also been reported.…”

Section: Intrarenal Raasmentioning

confidence: 99%

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

Feldman

2010

Hypertens Res

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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.

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“…However, this is probably due primarily to mesangial RAS. Staining for ACE has been found to be enhanced in glomeruli and vasculature of diabetic rats and in patients with diabetic nephropathy (Mizuiri, S., 1998). These data suggest that the term "intrarenal" RAS is oversimplistic, in as much as the vascular RAS (vessels and glomeruli) appears to be regulated differently from the tubulointerstitial RAS.…”

Section: Renin-angiotensin System In Diabetic Nephropathymentioning

confidence: 90%