In 1972 Neal Bricker presented the “trade-off” hypothesis in which he detailed the role of physiological adaptation processes in mediating some of the pathophysiology associated with declines in renal function. In the late 1990’s Xie and Askari published seminal studies indicating that the Na+/K+-ATPase (NKA) was not only an ion pump, but also a signal transducer that interacts with several signaling partners. Since this discovery, numerous studies from multiple laboratories have shown that the NKA is a central player in mediating some of these long-term “trade-offs” of the physiological adaptation processes which Bricker originally proposed in the 1970’s. In fact, NKA ligands such as cardiotonic steroids (CTS), have been shown to signal through NKA, and consequently been implicated in mediating both adaptive and maladaptive responses to volume overload such as fibrosis and oxidative stress. In this review we will emphasize the role the NKA plays in this “trade-off” with respect to CTS signaling and its implication in inflammation and fibrosis in target organs including the heart, kidney, and vasculature. As inflammation and fibrosis exhibit key roles in the pathogenesis of a number of clinical disorders such as chronic kidney disease, heart failure, atherosclerosis, obesity, preeclampsia, and aging, this review will also highlight the role of newly discovered NKA signaling partners in mediating some of these conditions.
Objectives: To investigate possible side effects of ketoconazole and griseofulvin on fertility of clinically healthy male rabbits. Design: Randomized controlled experimental study. Animals: Thirty mature male rabbits. Procedures: Rabbits were randomly allocated into three equal sized groups (10 animals each). The first group served as a control group (received no treatment), the second group received griseofulvin (25 mg/kg B.W) orally for 30 days, and the third group received ketoconazole (50 mg/kg B.W) orally for 30 days. Semen samples were collected after 1 day, 1 week and 2 weeks post-administration to determine sperm motility, % of live and dead sperms, total sperm abnormalities and sperm cell concentration. Two weeks post-administration, testes and epididymides were removed for histopathological examination. Results: Both drugs produced a significant reduction in the serum testosterone level, sperm cell concentration, percent of live sperms and percent of sperm motility. Conclusion and clinical relevance: Ketoconazole and griseofulvin have a negative impact on fertility of male rabbits, and the effect is more pronounced with ketoconazole.
Background Recent studies have highlighted a critical role for a group of natriuretic hormones, cardiotonic steroid ( CTS ), in mediating renal inflammation and fibrosis associated with volume expanded settings, such as chronic kidney disease. Immune cell adhesion is a critical step in the inflammatory response; however, little is currently understood about the potential regulatory role of CTS signaling in this setting. Herein, we tested the hypothesis that CTS signaling through Na + /K + ‐ ATP ase α‐1 ( NKA α‐1) enhances immune cell recruitment and adhesion to renal epithelium that ultimately advance renal inflammation. Methods and Results We demonstrate that knockdown of the α‐1 isoform of Na/K‐ ATP ase causes a reduction in CTS ‐induced macrophage infiltration in renal tissue as well reduces the accumulation of immune cells in the peritoneal cavity in vivo. Next, using functional adhesion assay, we demonstrate that CTS‐ induced increases in the adhesion of macrophages to renal epithelial cells were significantly diminished after reduction of NKA α‐1 in either macrophages or renal epithelial cells as well after inhibition of NKA α‐1‐Src signaling cascade with a specific peptide inhibitor, pNaK tide in vitro. Finally, CTS‐ induced expression of adhesion markers in both endothelial and immune cells was significantly inhibited in an NKA α‐1‐Src signaling dependent manner in vitro. Conclusions These findings suggest that CTS potentiates immune cell migration and adhesion to renal epithelium through an NKA α‐1–dependent mechanism; our new findings suggest that pharmacological inhibition of this feed‐forward loop may be useful in the treatment of renal inflammation associated with renal disease.
T o inves tig ate poss ible s ide e ffe cts of ke tocona z ole a nd g ris e ofulvin on fertility of clinica lly healthy male rabbits . Design: Random iz e d controlle d experim e ntal study. Animals : Thirty mature male rabbits . Proce dure s: Ra bbits we re ra ndom ly a lloca te d into thre e e qua l siz e d g roups (10 a nimals ea ch). T he firs t g roup s e rve d as a control g roup (re ceive d no tre atm e nt), the s e cond group re ce ive d g ris e ofulvin (25 mg / kg B.W ) orally for 30 da ys , a nd the third g roup re ce ive d ke tocona z ole (50 mg / kg B.W ) ora lly for 30 da ys . Se m e n sa m ple s we re colle cte d afte r 1 da y, 1 we e k a nd 2 we e ks post -a dm inistra tion to de te rm ine s pe rm m otility, % of live a nd de a d s pe rm s , tota l s pe rm a bnorm a lities a nd s pe rm cell conce ntra tion. T wo we e ks pos t-a dm inis tration, tes tes a nd e pididym ides we re re m ove d for histopa tholog ica l examination. Re s ults: Both drug s produce d a sig nifica nt re duction in the se rum tes tos te rone le ve l, sperm cell concentra tion, percent of live sperms and percent of sperm motility. Conclus ion and clinical re le vance: Ke toconaz ole a nd g ris e ofulvin ha ve a ne ga tive impa ct on fertility of male rabbits , and the effect is more pronounce d with ketoconaz ole .
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