ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy

Groß, Marie-Luise; El-Shakmak, A.; Szabó, Antal; Koch, Andreas; Kuhlmann, Alexander; Münter, Klaus; Ritz, Eberhard; Amann, Kerstin

doi:10.1007/s00125-003-1106-8

Cited by 106 publications

(31 citation statements)

References 38 publications

(45 reference statements)

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“…It is possible that in less severely affected patients, only diseased podocytes with low WT-1 expression are shed into the urine, while in patients with advanced diabetic nephropathy, even ‘normal’ podocytes with preserved WT-1 expression are lost. It should be noted that previous studies on urinary podocytes usually focus on the level of podocyte loss rather than the qualitative change of the podocytes being shed [36,37,38]. Because the number of subjects in this study was small, we cannot exclude the possibility that the urinary mRNA expression of other podocyte-associated molecules may also be correlated with the degree of histological damage.…”

Section: Discussionmentioning

confidence: 61%

Messenger RNA Expression of Podocyte-Associated Molecules in the Urinary Sediment of Patients with Diabetic Nephropathy

Wang

Lai²,

Lai³

et al. 2007

Nephron Clin Pract

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Background: Podocyte loss plays an important role in the pathogenesis of diabetic nephropathy. We hypothesize that messenger RNA expression of podocyte-associated molecules in urinary sediment may provide important clinical information in patients with diabetic nephropathy. Method: We studied 21 patients with biopsy-proven diabetic nephropathy and 9 healthy controls. The mRNA expression of nephrin, podocin, synaptopodin, Wilms’ tumor-1 (WT-1) and α-actinin-4 in urinary sediment were measured by real-time quantitative polymerase chain reaction. The degree of histological damage was quantified by morphometric analysis. Patients were then followed for an average of 25.63 ± 10.76 months. The rate of glomerular filtration rate (GFR) decline was calculated by the least-square regression. Results: There were significant differences in nephrin, podocin, synaptopodin, α-actinin-4 (p < 0.01 for all comparisons) and WT-1 (p = 0.028) expression between patients and normal controls. Urinary nephrin expression was significantly correlated with proteinuria (r = 0.502, p = 0.020); urinary synaptopodin was significantly correlated with proteinuria (r = 0.585, p = 0.005), serum creatinine (r = 0.516, p = 0.017) and estimated GFR (r = –0.560, p = 0.008), and urinary WT-1 expression was significantly correlated with the degree of tubulointerstitial fibrosis (r = 0.558, p = 0.009). There was no significant correlation between GFR decline and urinary expression of target genes. Conclusion: Urinary mRNA expressions of nephrin, podocin, synaptopodin, WT-1 and α-actinin-4 are higher in patients with diabetic nephropathy than in normal controls. Urinary nephrin and synaptopodin expressions are correlated with baseline clinical parameters such as proteinuria or renal function, while WT-1 expression is related to the degree of histological damage. Our results suggest that urinary mRNA expression of podocyte-associated molecules may be used for risk stratification of diabetic nephropathy.

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Section: Discussionmentioning

confidence: 61%

Messenger RNA Expression of Podocyte-Associated Molecules in the Urinary Sediment of Patients with Diabetic Nephropathy

Wang

Lai²,

Lai³

et al. 2007

Nephron Clin Pract

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“…Zhang et al [17] found that losartan, perindopril, and captopril could block high glucose induced hypertrophy in rat proximal tubular cells. Gross et al [18] found that trandolapril could prevent podocyte hypertrophy and degeneration in STZ-induced diabetic rats and, consequently, prevent the development of albuminuria. Studies had shown that AngII induced proliferation requiring a complete cell progression through the various steps of the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Connective Tissue Growth Factor-Mediated Angiotensin II-Induced Hypertrophy of Proximal Tubular Cells

Liu¹,

Chen²,

Sun³

et al. 2005

Nephron Exp Nephrol

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Background: Cellular hypertrophy is an early, important pathological feature of renal diseases such as diabetic nephropathy and remnant kidney. Recent studies have demonstrated that angiotensin II (AngII) plays a key role in mediating cell hypertrophy. The aim of our work was to explore the role of connective tissue growth factor (CTGF) in mediating AngII-induced tubular cell hypertrophy in vivoandin vitro. Methods: In an in vivo study, male Sprague-Dawley rats were randomly divided into three groups: control rats, diabetic rats and diabetic rats treated with irbesartan (IRB). The index of kidney hypertrophy (kidney weight/body weight, KW/BW), glomerular tuft area (A_G), glomerular tuft volume (V_G) and proximal tubular area (A_T) were determined. Renal expression for CTGF was detected by immunohistochemical staining. In an in vitro study, the influence of CTGF antisense oligonucleotide (CTGF AS) on AngII-induced CTGF expression and cell hypertrophy was also investigated. Results:In an in vivo study, diabetic rats showed a significant increase of KW/BW, A_G, V_G, and A_T from week 1 onwards compared to normal control, which could be significantly inhibited by using IRB. Furthermore, there was a significantly increasing expression of CTGF in both glomeruli and tubuli in diabetic rats compared to control, and the extent of CTGF expression closely correlated with the severity of renal hypertrophy. Treatment with IRB could markedly inhibit the renal expression of CTGF. In an in vitro study, AngII stimulated the expression of CTGF mRNA and CTGF protein. AngII significantly increased the total protein content in HK2 cells, which was markedly inhibited by co-treatment with CTGF AS. The average cellular diameter determined by scanning electronic microscope showed that the increase of cell size induced by AngII could be significantly inhibited by CTGF AS. Furthermore, flow cytometer study showed that AngII arrested the cell cycle in the G0-G1 phase, which was significantly reversed by treatment with CTGF AS. Conclusion: Our data provide both in vivo and in vitroevidence that CTGF is involved in mediating AngII-induced renal hypertrophy.

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“…Each score reflects changes in the extent rather than the intensity of staining and depends on the percentage of positive glomeruli. The degree of MDA and NDUFS3 expression in ten rats from each group was graded as follows: 0, absent or !25% staining; 1, 25-50% positive staining; 2, 50-75% positive staining; and 3, more than 75% positive staining (Gross et al 2003).…”

Section: Immunohistochemistry Stainingmentioning

confidence: 99%

Telmisartan improves kidney function through inhibition of the oxidative phosphorylation pathway in diabetic rats

Zhang

Xiao²,

Li³

et al. 2012

Journal of Molecular Endocrinology

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Telmisartan provides renal benefit at all stages of the renal continuum in patients with type 2 diabetes mellitus. This research is to investigate the effect of telmisartan on kidney function in diabetic rats and to identify the underlying molecular mechanisms. Diabetic rats were divided into vehicle group, low dosage (TeL) group, and high dosage of telmisartan (TeH) group. We performed Illumina RatRef-12 Expression BeadChip gene array experiments. We found 3-months of treatment with telmisartan significantly decreased 24-h urinary albumin, serum creatinine, blood urea nitrogen, and increased creatinine clearance rate. Kidney hypertrophy and glomerular mesangial matrix expansion were ameliorated. The glomeruli from the TeH group had 1541 genes with significantly changed expression (554 increased, 987 decreased). DAVID (Database for annotation, visualization and Integrated discovery) analyses showed that the most enriched term was 'mitochondrion' (Gene Ontology (GO:0005739)) in all 67 GO functional categories. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that all differentially expressed genes included seven KEGG pathways. Of those pathways, four are closely related to the oxidative phosphorylation pathway. Quantitative real-time PCR verified that the H+ transporting mitochondrial F1 complex, beta subunit (Atp5b), cytochrome c oxidase subunit VIc (Cox6c), and NADH dehydrogenase (ubiquinone) Fe-S protein 3 (Ndufs3) were significantly downregulated both in TeL and TeH groups, while nephrosis 1 homolog (Nphs1) and nephrosis 2 homolog (Nphs2) were significantly upregulated. The increased expression of malonaldehyde and NDUFS3 in the glomeruli of diabetic rats was attenuated by telmisartan. The other significantly changed pathway we found was the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Our data suggest that telmisartan can improve kidney function in diabetic rats. The mechanism may be involved in mitochondrion oxidative phosphorylation, the PPAR-g pathway, and the slit diaphragm.

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ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy

Cited by 106 publications

References 38 publications

Messenger RNA Expression of Podocyte-Associated Molecules in the Urinary Sediment of Patients with Diabetic Nephropathy

Messenger RNA Expression of Podocyte-Associated Molecules in the Urinary Sediment of Patients with Diabetic Nephropathy

Connective Tissue Growth Factor-Mediated Angiotensin II-Induced Hypertrophy of Proximal Tubular Cells

Telmisartan improves kidney function through inhibition of the oxidative phosphorylation pathway in diabetic rats

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