Norbert Wendt

Charité Universitätsmedizin Berlin, Berlin, Land Berlin, Germany

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Publications (7)28.88 Total impact

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    ABSTRACT: We investigated whether alterations of transient receptor potential canonical (TRPC) channel expression may be observed in tissues from Munich Wistar Frömter (MWF) rats showing proteinuria compared to control Wistar rats. TRPC expression was investigated in tissue from MWF and Wistar rats using quantitative real time PCR, immunoblotting, and immunohistochemistry. Compared to Wistar rats MWF rats showed significantly increased systolic blood pressure and significantly higher left ventricle weight (each p < 0.01). Quantitative real time PCR revealed that TRPC3 transcripts were significantly higher in kidney cortex from MWF rats compared to Wistar rats (p < 0.01). TRPC3 transcripts were not significantly different in kidney medulla nor in aorta from both groups (p = n.s.). Furthermore, TRPC6 transcripts were significantly lower in kidney cortex from MWF rats compared to Wistar rats (p < 0.001). Immunoblotting showed that TRPC3 channel protein expression was also significantly higher in kidney cortex from MWF rats compared to Wistar rats (p < 0.01). There was a significant correlation of TRPC3 mRNA and a specific marker for endothelium, von Willebrand factor (vWF; Spearman r = 0.564; p < 0.01). We observed a significant correlation between the TRPC3 transcripts to TRPC6 transcripts ratio in kidney cortex and urinary albumin excretion (Spearman r = 0.785, p < 0.001). Altered TRPC expression pattern in kidney cortex is associated with kidney damage in MWF rats showing hypertension and albuminuria.
    American Journal of Nephrology 10/2009; 31(1):36-44. · 2.62 Impact Factor
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    ABSTRACT: Previously we confirmed an important role of rat chromosome 19 (RNO19) for salt-sensitive hypertension and target organ damage in male Dahl salt-sensitive rats (SS rats). The aim of this study was to further analyse the basis of left ventricular (LV) fibrosis development in both male and female rats in this model. To this end we utilized a consomic SS-19(SHR) rat strain in which RNO19 was transferred from spontaneously hypertensive rats (SHR) into the susceptible background of SS. We compared the effects of low- (0.2% NaCl) and high-salt (4% NaCl) diet on the development of hypertension, blood lipids and LV fibrosis in male and female SS, SHR, and SS-19(SHR) rats. Systolic blood pressure was significantly lower in male and female SS-19(SHR) compared with SS under both diets (P < 0.001). Relative LV weight was similarly reduced in SS-19(SHR) compared with SS in either sex. Plasma cholesterol concentrations were significantly elevated in high-salt fed male and female SS (141 +/- 6 and 110 +/- 7 mg/dL) compared with SHR (47 +/- 2 and 62 +/- 8 mg/dL, P < 0.001) and were significantly lowered in male and female consomic rats (100 +/- 7 and 87 +/- 3 mg/dL). Both LV interstitial fibrosis (LVIF) and perivascular fibrosis (LVPF) were significantly reduced in high-salt male and female SS-19(SHR). A significant correlation between cholesterol concentrations and LVPF (r = 0.464) and LVIF (r = 0.401, P < 0.0001, respectively) was detected. Fibrosis parameters demonstrated no correlation with blood pressure, LV weight or plasma triglycerides concentrations. LV immunohistochemistry analysis showed a significant higher number of ED-1 positive cells in SS compared with SS-19(SHR). Depositions of collagen I and fibronectin were also greater in LV tissue of SS compared with SS-19(SHR). Our findings point to a link between hypercholesterolemia and LV fibrosis in salt-sensitive hypertension of SS rats which is genetically modulated by RNO19.
    Cardiovascular research 10/2008; 81(3):618-26. · 5.80 Impact Factor
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    ABSTRACT: The Munich Wistar Frömter (MWF) rat represents a genetic model with an inherited nephron deficit and exhibits mild hypertension and progressive albuminuria, which is more pronounced in males than females. Previously, we demonstrated in a consomic strain that replacement of a quantitative trait locus on chromosome 6 normalized the nephron deficit and suppressed albuminuria development, suggesting a link between the two findings. Here we tested the role of a second major locus linked to albuminuria in MWF on chromosome 8 and generated the consomic strain MWF-8(SHR) by transfer of chromosome 8 from spontaneously hypertensive rats (SHR) into MWF. The early onset of albuminuria at 8 wk of age in MWF (>50-fold increase compared with SHR) was significantly suppressed in consomic animals, and the development of marked proteinuria at 32 wk significantly diminished. Total nephron number in consomic rats (23,771 +/- 1,352) and MWF (27,028 +/- 1,322) were similar and significantly lower (-36%) compared with SHR (36,979 +/- 1,352, P < 0.0001). The development of mild albuminuria in female MWF was also significantly diminished in MWF-8(SHR). Thus, the development of overt and mild albuminuria in male and female MWF rats is not a mandatory consequence of the inherited nephron deficit. The locus on chromosome 8 appears of interest, because its exchange between MWF and SHR protects against the development of albuminuria in MWF-8(SHR) animals despite their inherited nephron deficit and higher systolic blood pressure.
    Physiological Genomics 09/2008; 35(1):30-5. · 2.81 Impact Factor
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    ABSTRACT: Clinical and experimental studies indicate that the progression of renal disease is faster in males than females. These observations are corroborated by a sexual dimorphism observed in the polygenetic MWF (Munich Wistar Frömter) rat model. The age-dependent spontaneous progression of increased UAE (urinary albumin excretion) in male MWF rats is influenced by multiple QTLs (quantitative trait loci). In contrast, female MWF rats only develop a slight increase in UAE, while the role of genetic factors for this phenotype is unknown. In the present study, we show that, compared with resistant SHRs (spontaneously hypertensive rats), both male and female MWF rats develop a significant increase in UAE at 24 weeks of age (P<0.0001), although blood pressures were lower compared with SHRs (P<0.0001). UAE was significantly higher in male (7-fold) compared with female MWF rats (162.6+/-15.9 compared with 24.0+/-5.5 mg/24 h respectively; P<0.0001), and only male MWF rats developed significant glomerulosclerosis and tubulointerstitial damage in the kidney (P<0.0001). To test the role of genetic factors in the development of low grade albuminuria in female MWF rats, we analysed the role of a major UAE QTL on rat chromosome 6. To this end, we analysed a consomic MWF-6(SHR) strain in which chromosome 6 from SHRs was introgressed into the MWF rat background. Time course analysis of UAE in females indicated that the small increase in UAE in MWF rats was fully suppressed by exchange of rat chromosome 6. Thus, taken together with previous studies in males, we show that RNO6 protects against the increase in albuminuria with age in both female and male MWF rats.
    Clinical Science 02/2008; 114(4):305-11. · 4.86 Impact Factor
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    ABSTRACT: In a cross between the Munich Wistar Frömter (MWF) rat and spontaneously hypertensive rats (SHR), a major quantitative trait locus (QTL) was identified on rat chromosome 6 (RNO6) that demonstrated the strongest linkage to albuminuria among several QTL identified. The QTL represented the only locus that is linked to both early-onset albuminuria and increased renal interstitial fibrosis in adult animals. A consomic MWF-6(SHR) strain in which chromosome 6 from SHR was introgressed into the MWF background therefore was generated to test the relevance of this QTL. Phenotype analysis at 8 wk of age revealed that early onset of albuminuria in MWF with a 55-fold elevation of urinary albumin excretion compared with SHR (P < 0.0001) was completely abolished in MWF-6(SHR). Time-course analysis until week 24 demonstrated only a moderate increase of urinary albumin excretion in MWF-6(SHR), whereas MWF reached levels in the nephrotic range (16.6 +/- 3.5 versus 162.6 +/- 16.0 mg/24 h; P < 0.0001). At this age, analysis of glomerulosclerosis, tubulointerstitial damage, renal interstitial fibrosis, and renal collagen III mRNA expression revealed a significant improvement of all parameters in MWF-6(SHR) compared with MWF (P < 0.05). At 32 wk, MWF but not MWF-6(SHR) demonstrated overt proteinuria (354.6 +/- 37.6 versus 48.8 +/- 13.2; P < 0.0001), whereas serum urea, cholesterol, and triglyceride concentrations were lower and creatinine clearance was higher in MWF-6(SHR) compared with MWF (P < 0.05). Therefore, although albuminuria in MWF is determined by a complex interplay of several QTL, our data demonstrate that genetic exchange of one locus on RNO6 leads to marked suppression of early-onset albuminuria and renal damage in MWF.
    Journal of the American Society of Nephrology 02/2007; 18(1):113-21. · 8.99 Impact Factor
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    ABSTRACT: Unlike Dahl salt-sensitive (SS) rats, some strains of spontaneously hypertensive (SHR) rats develop only minor organ damage even when exposed to high-salt diet. In previous linkage studies, we identified quantitative trait loci on rat chromosome 19 (RNO19) linked to the SHR allele suggesting a protective effect against salt-induced hypertensive organ damage in SS. To test the relevance of this finding, we generated and characterized a consomic strain SS-19SHR in which RNO19 from SHR was introgressed into the susceptible background of SS. We compared the effects of low-salt (0.2% NaCl) and high-salt (4% NaCl) diet exposure for 8 weeks on the development of hypertension and target organ damage in male consomic and SS animals (n=14-20, each). Systolic blood pressure, relative left ventricular weight and urinary protein excretion were significantly lower in SS-19SHR compared to SS under both low-salt and high-salt diet (P < 0.05, respectively). Left ventricular atrial natriuretic peptide mRNA expression showed a more pronounced 4.5-fold increase in SS compared to SS-19 (two-fold) after high-salt (P < 0.05). In comparison to low diet, high-salt exposure induced a significant increase in vascular aortic hypertrophy index, left ventricular interstitial fibrosis (+210%) and perivascular fibrosis (+195%) in SS but not in consomic SS-19SHR (P < 0.05, respectively). These results demonstrate a strong protective effect of RNO19 from SHR on the development of hypertension, salt-sensitivity, cardiovascular and renal organ damage in SS. In particular, we demonstrate a genetic effect protecting against the development of cardiac fibrosis in salt-sensitive hypertension.
    Journal of Hypertension 02/2007; 25(1):95-102. · 3.81 Impact Factor
  • Journal of The American Society of Nephrology - J AMER SOC NEPHROL. 01/2007; 18(1):113-121.