Anna Lely

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Severe acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS‐CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin‐converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS‐CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS‐CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations. Copyright

Sodium status and angiotensin-converting enzyme inhibition: effects on plasma angiotensin-(1-7) in healthy man.

Objective Angiotensin-converting enzyme (ACE) inhibitors provide effective intervention for cardiovascular and renal disease. Changes in angiotensin-(1-7) have been proposed to be involved in the mechanism of action of ACE inhibition (ACEi). In particular, an altered balance between angiotensin II and angiotensin-(1-7) might be involved. A shift in sodium status modifies the activity of the renin–angiotensin–aldosterone system and the effects of ACEi, but its effects on angiotensin-(1-7) are unknown. We therefore studied the effect of a shift in sodium intake on angiotensin-(1-7), during placebo and ACEi. Methods A double-blind, placebo-controlled study was conducted in 17 healthy men. The subjects were studied for two 2-week periods: 20 mg/day enalapril and placebo. The first week of each period they used a 50 mmol Na+ diet [low sodium (LS)], the second week a 200 mmol Na+ diet. Angiotensin levels and blood pressure were measured at the end of each week. Results During placebo, LS intake elicited a three-fold rise in ang-(1-7) that paralleled the rise in other components of the renin–angiotensin system. During ACEi LS did not affect angiotensin II, but did induce a clear-cut rise in angiotensin-(1-7) — to the extent that angiotensin-(1-7) was highest during combination of ACEi and LS. Consequently, during ACEi LS shifted the balance between angiotensin-(1-7) and angiotensin II towards angiotensin-(1-7). Conclusion The sodium status modifies levels of angiotensin-(1-7). During ACEi angiotensin-(1-7) is still subject to stimulation by sodium restriction, and provides opportunity for therapeutic manipulation. Exploration of this opportunity in patient populations may lead to strategies to improve therapeutic benefits of ACEi.

Hydrogen sulfide producing enzymes in pregnancy and preeclampsia

Preeclampsia, a human pregnancy specific disorder is characterized by an anti-angiogenic state. As hydrogen sulfide (H(2)S) has pro-angiogenic and anti-oxidative characteristics, we hypothesized that H(2)S levels could play a role in the pathogenesis of preeclampsia and studied the placental expression of the H(2)S-producing enzymes cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS). CBS and CSE protein are expressed in the fetal-placental endothelium and CBS only in Hofbauer cells. CBS mRNA expression is decreased (p = 0.002) in early-onset preeclampsia, while CSE mRNA is unchanged. Thus, down regulation of CBS during early-onset preeclampsia may result in less H(2)S-production and may aid in the anti-angiogenic state.

Donor kidney adapts to body dimensions of recipient: no influence of donor gender on renal function after transplantation.

Female kidneys and kidneys from small donors have been suggested to perform worse after kidney transplantation. Here, we evaluate the impact of gender and body dimensions on posttransplantation GFR in living donor transplantation. Two hundred and ninety‐three donor–recipient pairs, who were transplanted at our center were evaluated. All pairs had detailed renal function measurement (125I‐iothalamate and 131I‐hippuran) 4 months predonation in the donor and 2.5 months posttransplantation in donor and recipient. For 88 pairs, 5 years of recipient follow‐up was available. Delta GFR was calculated as (recipient GFR–donor single kidney GFR). Recipients of both male and female kidneys had similar renal function at early and long term after transplantation. Male recipients had higher ERPF, ΔGFR and ΔERPF at both time points. Kidneys of donors smaller than their recipient had higher ΔGFR and ΔERPF than kidneys of larger donors at both time points (p < 0.05). In multivariate analysis, ΔGFR was predicted by donor/recipient BSA‐ratio together with transplantation related factors (R2 0.19), irrespective of donor and recipient gender. In conclusion, in living donor transplantation, female kidneys perform as well as male donor kidneys. Kidneys adapt to the recipients body size and demands, independent of gender, without detrimental effects in renal function and outcome up to mid‐long term.

Hemopexin activity is associated with angiotensin II responsiveness in humans.

Background: Hemopexin, an acute phase protein, can downregulate the angiotensin (ang) II type 1 receptor (AT1-R) in vitro. Whether hemopexin is involved in the responsiveness to ang II in vivo is unknown. Therefore, we tested whether variations in endogenous hemopexin activity are associated with the responsiveness of blood pressure to ang II in healthy volunteers. Method: Healthy men (n = 33, age 26 ± 9) were studied in balance on low sodium (50 mmol Na+ per 24 h) and high sodium (200 mmol Na+ per 24 h) diet, respectively. After baseline measurements of blood pressure, ang II was infused at 0.3, 1 and 3 ng/kg per min for 1 h per dose. Hemopexin activity was measured at baseline in EDTA–plasma samples by an amidolytic assay with a chromogenic substrate suitable for hemopexin activity evaluation. Results: During high sodium the hemopexin activity was lower; 1.6 × 105 (0.6 × 105 − 4.7 × 105) versus 2.8 × 105 (1.1 × 105 − 5.1 × 105) arbitrary units (P < 0.01) and the pressor response to 3 ng ang II/kg per minute larger than during low sodium (17.6 ± 6.5 versus 14.6 ± 6.9 mmHg, P < 0.01). Hemopexin activity negatively correlated with the pressor response to ang II during either type of sodium intake (high sodium: r = 0.42, P < 0.05; low sodium: r = 0.35, P < 0.05). Conclusion: These in-vivo data obtained in healthy individuals support recent in-vitro data showing that active hemopexin downregulates the availability of the AT1-R. Therefore, activated hemopexin might be considered as a factor mediating ang II effects upon blood pressure by modulating AT1-R availability.

Donor Kidney Adapts to Body Dimensions of Recipient

Female kidneys and kidneys from small donors have been suggested to perform worse after kidney transplantation. Here, we evaluate the impact of gender and body dimensions on posttransplantation GFR in living donor transplantation. Two hundred and ninety‐three donor–recipient pairs, who were transplanted at our center were evaluated. All pairs had detailed renal function measurement (125I‐iothalamate and 131I‐hippuran) 4 months predonation in the donor and 2.5 months posttransplantation in donor and recipient. For 88 pairs, 5 years of recipient follow‐up was available. Delta GFR was calculated as (recipient GFR–donor single kidney GFR). Recipients of both male and female kidneys had similar renal function at early and long term after transplantation. Male recipients had higher ERPF, ΔGFR and ΔERPF at both time points. Kidneys of donors smaller than their recipient had higher ΔGFR and ΔERPF than kidneys of larger donors at both time points (p < 0.05). In multivariate analysis, ΔGFR was predicted by donor/recipient BSA‐ratio together with transplantation related factors (R2 0.19), irrespective of donor and recipient gender. In conclusion, in living donor transplantation, female kidneys perform as well as male donor kidneys. Kidneys adapt to the recipients body size and demands, independent of gender, without detrimental effects in renal function and outcome up to mid‐long term.

Donor Kidney Adapts to Body Dimensions of Recipient: No Influence of Donor Gender on Renal Function After Transplantation: Kidneys Adapt to Body Size Irrespective of Gender

Female kidneys and kidneys from small donors have been suggested to perform worse after kidney transplantation. Here, we evaluate the impact of gender and body dimensions on posttransplantation GFR in living donor transplantation. Two hundred and ninety‐three donor–recipient pairs, who were transplanted at our center were evaluated. All pairs had detailed renal function measurement (125I‐iothalamate and 131I‐hippuran) 4 months predonation in the donor and 2.5 months posttransplantation in donor and recipient. For 88 pairs, 5 years of recipient follow‐up was available. Delta GFR was calculated as (recipient GFR–donor single kidney GFR). Recipients of both male and female kidneys had similar renal function at early and long term after transplantation. Male recipients had higher ERPF, ΔGFR and ΔERPF at both time points. Kidneys of donors smaller than their recipient had higher ΔGFR and ΔERPF than kidneys of larger donors at both time points (p < 0.05). In multivariate analysis, ΔGFR was predicted by donor/recipient BSA‐ratio together with transplantation related factors (R2 0.19), irrespective of donor and recipient gender. In conclusion, in living donor transplantation, female kidneys perform as well as male donor kidneys. Kidneys adapt to the recipients body size and demands, independent of gender, without detrimental effects in renal function and outcome up to mid‐long term.