Immunization with ACE (Angiotensin Converting Enzyme) Develops Diabetic Changes in the Kidney and Retina in Diabetogenic Rats

Nishida, Seikoh; Sasaki, Tatsuya; Kimura, Hisashi; Tanaka, Junji; Nohno, Tsutomu; Hirokawa, Yasushi; Matsuki, Michihiro; Ichihara, Kiyoshi

doi:10.1507/endocrj.50.801

Cited by 6 publications

(10 citation statements)

References 14 publications

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“…Recently, the possibility of autoantibodies to ACE in diabetic patients has been suggested (35). The same group also demonstrated that immunization of rabbits and rats with ACE led to the development of atherosclerotic retinal changes and glomerular changes similar to those seen in diabetic nephropathy (36). Bearing in mind the presence of several mouse models of diabetes, awareness of the potential loss of natural antigenicity or the appearance of non‐natural epitopes on mouse ACE by minor denaturation during an adsorption on plastic will be essential for searching for autoantibodies to mouse ACE in these mouse models.…”

Section: Discussionmentioning

confidence: 83%

Development and characterization of rat monoclonal antibodies to denatured mouse angiotensin‐converting enzyme

et al. 2005

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Four new rat monoclonal antibodies, generated to denatured mouse somatic angiotensin-converting enzyme (ACE, CD143), detect mouse ACE with high sensitivity in Western blotting. Epitope mapping for the monoclonal antibodies--B12, 4G6 and 5C4--was also performed. Two monoclonal antibodies--B12 and 5C4--are directed to various epitopes on the N-domain--i.e., they recognized only the somatic isoform of mouse ACE. The monoclonal antibody H7 recognized an epitope on the C-domain of mouse ACE. The monoclonal antibody 4G6 was directed to a sequence on the N-domain of mouse ACE, which is homologous to a region of the C-domain and, as a result, also recognizes mouse testicular ACE (tACE) by means of Western blotting. In paraffin-embedded mouse tissues, all monoclonal antibodies detected all known expression sites of somatic ACE (sACE), e.g., the epithelial cells of the kidney proximal tubules, intestine and epididymis, and heterogeneously in endothelial cells. The monoclonal antibodies 4G6 and H7 additionally stained mouse tACE in spermatozoa and in mature spermatids. The monoclonal antibody 4G6 also demonstrated cross-reactivity with sACE from a broad spectrum of animal species, including human, rat, rabbit and bovine. However, this monoclonal antibody did not recognize the testicular isoform of ACE of these species. This set of monoclonal antibodies is useful for identifying even subtle changes in mouse ACE conformation because of denaturation. These monoclonal antibodies are also sensitive tools for the detection of mouse ACE in biological fluids and tissues by using proteomics approaches. Their high reactivity in paraffin-embedded tissues opens up opportunities to study possible changes in the pattern of ACE expression in knockout mouse models and may prove useful for correlating ACE expression in these models with human diseases.

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Section: Discussionmentioning

confidence: 83%

Development and characterization of rat monoclonal antibodies to denatured mouse angiotensin‐converting enzyme

et al. 2005

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“…These findings are particularly relevant with respect to the concepts and standardization of immunoassays in which human ACE antigen will be used. Nishida et al (49) suggested the possibility of auto‐antibodies to ACE in diabetic patients and also showed that immunization of rabbits and rats with ACE led to the development of atherosclerotic retinal and glomerular changes similar to those seen in diabetic nephropathy (50). The extremely high sensitivity of mAb 3C5, which can recognize 1–2 ng of human ACE in Western blotting, raises the possibility of detecting and quantifying human ACE in biological fluids, such as cerebrospinal fluid (51) or urine (52, 53), without the need for enrichment (27, 28).…”

Section: Discussionmentioning

confidence: 99%

Epitope mapping of mAbs to denatured human testicular ACE (CD143)

et al. 2008

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Angiotensin I-converting enzyme (ACE; CD143) has two homologous enzymatically active domains (N and C) and plays a crucial role in blood pressure regulation and vascular remodeling. A wide spectrum of monoclonal antibodies (mAbs) to different epitopes on the N and C domains of human ACE have been used to study different aspects of ACE biology. In this study, we characterized a set of nine mAbs, developed against the C domain of human ACE, which recognize the denatured forms of ACE and thus are suitable for the detection and quantification of somatic ACE (sACE) and testicular ACE (tACE) using Western blotting and immunohistochemistry on paraffin-embedded human tissues. The epitopes for these mAbs were defined using species cross-reactivity, phage display library screening, Western blotting and ACE mutagenesis. Most of the mAbs recognized common/overlapping region(s) on both somatic and testicular forms of human ACE, whereas mAb 4E10 was relatively specific for the testicular isoform and mAb 5B9 mainly recognized the glycan attached to Asn 731. This set of mAbs is useful for identifying even subtle changes in human ACE conformation because of denaturation. These mAbs are also sensitive tools for the detection of human sACE and tACE in biological fluids and tissues using proteomic approaches. Their high reactivity in paraffin-embedded tissues provides opportunities to study changes in the pattern of ACE expression and glycosylation (particularly with mAb 5B9) in different tissues and cells.

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“…The antibodies were positive for 64.5% of the patients with diabetes and were positive in 83.3% in the early stage of clinical diabetic nephropathy. In addition, in genetically diabetogenic OLETF ( Otsuka Long-Evans Tokushima Fatty ) rats 2 , one of the characteristics of which strain is spontaneous nephropathy resembling those of human type 2 diabetes, and in control LETO rats 2 , immunization with rabbit lung ACE developed glomerulopathy similar to that seen in diabetics 3 . Also, in normal New Zealand white rabbits, immunization with the rabbit lung ACE induced glomerular changes similar to those seen in diabetic nephropathy 3 .…”

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confidence: 99%

“…In addition, in genetically diabetogenic OLETF ( Otsuka Long-Evans Tokushima Fatty ) rats 2 , one of the characteristics of which strain is spontaneous nephropathy resembling those of human type 2 diabetes, and in control LETO rats 2 , immunization with rabbit lung ACE developed glomerulopathy similar to that seen in diabetics 3 . Also, in normal New Zealand white rabbits, immunization with the rabbit lung ACE induced glomerular changes similar to those seen in diabetic nephropathy 3 . In this study, renal tissues identical to those examined in research of diabetic nephropathy by PAS staining and electron microscope in preceding study 3 , were examined by immunostaining methods, only to prove that the diabetic glomerular changes may occur by immunization with ACE, not by non-specific responses to ACE, in non-diabetogenic rats and rabbits.…”

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confidence: 99%

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Spontaneous glomerular deposition of immunoglobulins for ACE (Angiotensin Converting Enzyme) induces spontaneous nephropathy in diabetogenic rats

et al. 2009

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We first discovered autoantibodies to ACE (angiotensin converting enzyme) in patients with type 2 diabetes mellitus^1^. The antibodies were positive for 64.5% of the patients with diabetes and were positive in 83.3% in the early stage of clinical diabetic nephropathy. In addition, in genetically diabetogenic OLETF (Otsuka Long-Evans Tokushima Fatty) rats^2^, one of the characteristics of which strain is spontaneous nephropathy resembling those of human type 2 diabetes, and in control LETO rats^2^, immunization with rabbit lung ACE developed glomerulopathy similar to that seen in diabetics^3^. Also, in normal New Zealand white rabbits, immunization with the rabbit lung ACE induced glomerular changes similar to those seen in diabetic nephropathy^3^. In this study, renal tissues identical to those examined in research of diabetic nephropathy by PAS staining and electron microscope in preceding study^3^, were examined by immunostaining methods, only to prove that the diabetic glomerular changes may occur by immunization with ACE, not by non-specific responses to ACE, in non-diabetogenic rats and rabbits.

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Immunization with ACE (Angiotensin Converting Enzyme) Develops Diabetic Changes in the Kidney and Retina in Diabetogenic Rats

Cited by 6 publications

References 14 publications

Development and characterization of rat monoclonal antibodies to denatured mouse angiotensin‐converting enzyme

Development and characterization of rat monoclonal antibodies to denatured mouse angiotensin‐converting enzyme

Epitope mapping of mAbs to denatured human testicular ACE (CD143)

Spontaneous glomerular deposition of immunoglobulins for ACE (Angiotensin Converting Enzyme) induces spontaneous nephropathy in diabetogenic rats

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