Phenotypic Modulation of the Mesangium Reflected by Contractile Proteins in Diabetes

Makino, Hírofumi; Kashihara, Naoki; Sugiyama, Hitoshi; Kanao, Koichiro; Sekikawa, Takashi; Okamoto, Kazunori; Maeshima, Yohei; Ota, Zensuke; Nagai, Ryozo

doi:10.2337/diab.45.4.488

Cited by 78 publications

(30 citation statements)

References 35 publications

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“…Recently, Doi et al [29]demonstrated that overexpression of CNP in cultured SMCs by adenovirus-mediated gene transfer caused growth inhibition of SMCs at the G1 phase with phenotype modulation. GMC phenotype change has been suggested to be associated with glomerular hypercellularity and sclerosis [30, 31]. CNP may exert its suppressive effects such as antiproliferative action and inhibition of type IV collagen secretion by changing GMC phenotype.…”

Section: Discussionmentioning

confidence: 99%

C-Type Natriuretic Peptide Inhibits Proliferation and Monocyte Chemoattractant Protein-1 Secretion in Cultured Human Mesangial Cells

Osawa

Yamabe

Kaizuka

et al. 2000

Nephron

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Background: Mesangial cell proliferation and matrix accumulation are hallmarks of various progressive glomerular diseases. We examined whether C-type natriuretic peptide (CNP) that is known to regulate the proliferation of vascular smooth muscle cells could modulate these pathological processes using human glomerular mesangial cells (GMCs) in culture. Methods: Proliferation of GMCs cultured with different concentrations of CNP-22 for 48 h was determined by a colorimetric assay using a tetrazorium salt. Monocyte chemoattractant protein-1 (MCP-1) and type IV collagen secretion into the culture media by GMCs in the presence or absence of CNP-22 were evaluated by ELISA. Expression of mRNA for natriuretic peptide receptor B (NPR-B), a specific receptor for CNP, was examined by reverse transcription polymerase chain reaction (RT-PCR). Results: CNP-22 (1–10 µM) inhibited serum-induced GMC growth in a dose-dependent manner. The amount of MCP-1 in the culture supernatant was increased approximately 2.4-fold by 5 µg/ml of lipopolysaccharide. This increase was inhibited by CNP-22 at 0.1–1 µM in a dose-dependent fashion. CNP-22 (10 µM) inhibited GMC type IV collagen secretion stimulated by 20 ng/ml of platelet-derived growth factor. Expression of NPR-B mRNA was confirmed in GMCs by RT-PCR. Conclusions: CNP suppresses GMC proliferation and MCP-1 and type IV collagen secretion by GMCs. It may have a therapeutic potential against human proliferative glomerular diseases, especially those with the involvement of monocytes.

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Section: Discussionmentioning

confidence: 99%

C-Type Natriuretic Peptide Inhibits Proliferation and Monocyte Chemoattractant Protein-1 Secretion in Cultured Human Mesangial Cells

Osawa

Yamabe

Kaizuka

et al. 2000

Nephron

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“…Thirty glomeruli in each section were graded from 0 to 4+ by two blinded observers as follows: 0, none; 1, trace mesangial staining; 2, weak mesangial staining; 3, moderate mesangial staining; 4, strong mesangial staining, as previously reported [7]and data were mean ± SD.…”

Section: Methodsmentioning

confidence: 99%

“…They play physiologically important roles by supporting glomerular structure and controlling capillary tone [1, 2, 3]. In various glomerular diseases, phenotypic changes of MC have been observed in association with mesangial proliferation and interstitial collagen accumulation [4, 5, 6, 7, 8, 9, 10, 11]. This particular phenotype has been called ‘myofibroblast-like’, which is closely related to the progression of glomerular sclerosis [9, 10, 11].…”

Section: Introductionmentioning

confidence: 99%

“…Based on the similarities in cell shape and contractile property in response to angiotensin II or arginine vasopressin [12, 13, 14, 15], MC are thought to have the same origin as that of vascular smooth muscle cells (SMC) [1, 2]. During the phenotypic modulation, MC express α-smooth muscle actin (α-SMA), one of the contractile proteins expressed in vascular SMC [7, 8, 9, 10, 11]. To further characterize this phenotypic change, we focused on the expression of another contractile protein, caldesmon (CaD), in MC.…”

Section: Introductionmentioning

confidence: 99%

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Caldesmon Isoform Associated with Phenotypic Modulation of Mesangial Cells

Okamoto¹,

Kashihara²,

Yamasaki³

et al. 2000

Nephron Exp Nephrol

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Caldesmon (CaD) is a major calmodulin- and actin-binding protein distributed in smooth muscle cells (SMC) and nonmuscle cells. There are at least two high-molecular-weight CaD (h-CaD) isoforms and four low-molecular-weight CaD (l-CaD) isoforms produced by alternative splicing. Isoformal interconversion is associated with phenotypic modulations of vascular SMC. We investigated the CaD isoform in human and rat glomerular mesangial cells (MC) to characterize the phenotypic changes of MC involved in glomerular diseases. A Western blot analysis and reverse-transcription analysis using exon-specific primers revealed that one l-CaD isoform lacking exons 1, 3b and 4 was predominantly expressed in human cultured MC. The expression of this isoform was markedly enhanced in anti-Thy1.1 nephritis rats and streptozotocin-induced diabetic rats, while little expression was observed in the normal glomerulus. Isoformal interconversion did not occur during the phenotypic changes of MC. These data suggested that the activated MC resembled dedifferentiated SMC in terms of the CaD expression pattern, and that CaD is a useful marker of the phenotypic modulations of MC.

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“…The distribution of various ECM components and TGF-β was studied by using indirect immunofluorescence techniques as previously described [20]. …”

Section: Methodsmentioning

confidence: 99%

Accumulation of N<sup>σ</sup>-(Carboxy-methyl)lysine and Changes inGlomerular Extracellular MatrixComponents in Otsuka Long-EvansTokushima Fatty Rat:A Model of Spontaneous NIDDM

Kushiro

Shikata²,

Sugimoto

et al. 1998

Nephron

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Increases in extracellular matrix (ECM) and changes in its components have been documented in the glomeruli of diabetic nephropathy. Advanced glycation end products formed by glycoxidation have been shown to induce the synthesis of ECM components and transforming growth factor beta (TGF-β), suggesting that advanced glycation end products may be involved in the etiology of imbalance of ECM components in diabetic glomerulosclerosis. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an inbred strain that spontaneously develops non-insulin-dependent diabetes mellitus which progresses to diabetic glomerulosclerosis. N^Ε-(carboxymethyl)lysine (CML) is known to be formed by glycoxidation. To clarify the involvement of glycoxidation in diabetic nephropathy, we examined the localization of CML, ECM components, and TGF-β₁ in the glomeruli of OLETF rats. The amounts of α₃(IV) collagen, type VI collagen, and fibronectin were significantly increased in the glomeruli of OLETF rats, whereas the heparan sulfate proteoglycan levels were decreased. After 6 months of age, CML levels were significantly increased in the mesangial area of the glomeruli in these animals. The overexpression of TGF-β₁ preceded the increase in glomerular ECM components. The present study demonstrated that the accumulation of CML precedes the changes of glomerular ECM components in the glomeruli during the course of diabetic nephropathy, suggesting that glycoxidation may be one of the major causes of diabetic glomerulosclerosis.

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Phenotypic Modulation of the Mesangium Reflected by Contractile Proteins in Diabetes

Cited by 78 publications

References 35 publications

C-Type Natriuretic Peptide Inhibits Proliferation and Monocyte Chemoattractant Protein-1 Secretion in Cultured Human Mesangial Cells

C-Type Natriuretic Peptide Inhibits Proliferation and Monocyte Chemoattractant Protein-1 Secretion in Cultured Human Mesangial Cells

Caldesmon Isoform Associated with Phenotypic Modulation of Mesangial Cells

Accumulation of N<sup>σ</sup>-(Carboxy-methyl)lysine and Changes inGlomerular Extracellular MatrixComponents in Otsuka Long-EvansTokushima Fatty Rat:A Model of Spontaneous NIDDM

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