Search

1. The effects of volume depletion and NaHCO(3) loading on the expression of Na(+)/H(+) exchanger isoform 3 (NHE3), Na(+) : HCO(3)(-) cotransporter type 1 (NBC1) and neuronal (n) and inducible (i) isoforms of nitric oxide synthase (NOS) were determined in rat kidney. 2. Adult male Sprague-Dawley rats were used. Rats were divided into four groups: (i) euvolaemic (EC); (ii) hypovolaemic (HC); (iii) euvolaemia with NaHCO(3) loading (EB); and (iv) hypovolaemia with NaHCO(3) loading (HB). The expression of NHE3, NBC1, nNOS and iNOS proteins was determined in the cortex of the kidney by immunoblotting and immunohistochemistry. Tissue content of nitric oxide (NO) metabolites (NO(x)) were also determined in the cortex using a colourimetric assay. 3. Compared with the EC group, the expression of NHE3 and NBC1 was increased in the HC group and decreased in the EB group. Comparing the EB and HB groups, the expression of NHE3 and NBC1 was higher in the latter group. The expression of NHE3 was decreased and that of NBC1 was increased in the HB group compared with the HC group. The NO(x) content and nNOS expression were decreased in the hypovolaemic (HC) and NaHCO(3)-loaded (EB and HB) rats. Moreover, the expression of iNOS was decreased in the HB group compared with the other groups. 4. An altered volume status and NaHCO(3) loading may affect the regulation of NHE3 and NBC1 in the kidney and the endogenous NO system may play a role in the observed effects.

1. Effects of non-steroidal anti-inflammatory drugs on the local atrial natriuretic peptide (ANP) and nitric oxide (NO) systems in the kidney were investigated. 2. Male Sprague-Dawley rats were treated with indomethacin (5 mg/kg, every 12 h, i.p.) for 2 days. The expression of ANP and natriuretic peptide receptor-A (NPR-A) mRNA was determined in the kidney, as was that of endothelial NO synthase (NOS) proteins. Particulate and soluble guanylyl cyclase activities were determined separately. 3. Following treatment with indomethacin, urinary sodium excretion decreased significantly. Although the renal expression of ANP was not changed significantly, that of NPR-A decreased significantly. The expression of NOS increased significantly. Particulate guanylyl cyclase activity was decreased, whereas the activity of soluble guanylyl cyclase was increased. The catalytic activity of Na(+)/K(+)-ATPase was increased, with no significant changes in its expression. The expression of the type 3 Na/H exchanger and Na-K-2CL cotransporters increased significantly. 4. The indomethacin-induced decrease in urinary sodium excretion may be attributed, at least in part, to decreased activity of the local ANP/cGMP system. The increased activity of the NO/cGMP system may be a compensatory response to the diminished activity of the prostaglandin system.

Background information: Tubulointerstitial fibrosis is the end‐point of chronic kidney diseases. Tamoxifen, a selective oestrogen receptor (ER) modulator, attenuates renal fibrosis, by regulating the transforming growth factor (TGF)‐β/Smad signalling. Src and phosphoinositide 3‐kinase (PI3K)/Akt pathways play critical roles in the pathogenesis of renal fibrosis. However, the activation of the non‐canonical TGF‐β signalling in renal fibrosis after treatment with tamoxifen remains unclear. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) in rats. Tamoxifen was orally administered after UUO. Additionally, HK‐2 cells were treated with tamoxifen in the presence or absence of TGF‐β1. The selective ER down‐regulator ICI and ER‐α silencing were used to confirm the involvement of ER‐α on the effect of tamoxifen on TGF‐β1‐stimulated fibrosis in HK‐2 cells. Results: Tamoxifen treatment ameliorated UUO‐induced renal fibrosis as shown by decreased expression of α‐smooth muscle actin (SMA), fibronectin and connective tissue growth factor (CTGF). The phosphorylation of Src, PI3K, Akt, mammalian target of rapamycin (mTOR) and p70S6K significantly decreased in UUO kidneys from tamoxifen‐treated animals. Tamoxifen dose‐dependently suppressed the TGF‐β1‐induced expression of α‐SMA and CTGF, and phosphorylation of Src, PI3K, Akt, mTOR and p70S6K in HK‐2 cells. These anti‐fibrotic effects were reversed by treatment with ICI and silencing of ER‐α. Moreover, inhibition of the PI3K/Akt and mTOR/p70S6K pathways was observed in HK‐2 cells co‐treated with PP1 (a Src kinase inhibitor) and tamoxifen. Conclusions: The anti‐fibrotic effects of tamoxifen are associated with the suppression of Src kinase function via ER‐α, followed by inhibition of the PI3K/Akt and mTOR/p70S6K signalling pathways. Significance: Our findings suggest that tamoxifen is a novel therapeutic option for the prevention and treatment of renal fibrosis. Research Article: Our results demonstrated that phosphorylation of Src kinase in the obstructive kidney medicates renal fibrosis by activation of PI3K/Akt and mTOR/p70S6K signalling pathway, and treatment of tamoxifen has anti‐fibrotic effect on renal fibrosis by suppressing these pathways. In addition, our in vitro results suggested that anti‐fibrotic effect and its downstream signalling pathway were attenuated by tamoxifen in an ER‐α‐dependent manner. However, at present, it remains difficult to determine whether tamoxifen acts as anti‐oestrogenic or oestrogenic effect in our study. [ABSTRACT FROM AUTHOR]