Kidney-Brain Axis: In Renal Failure, Cardiotonic Steroids Stimulate Collagen-I in the Hypothalamus and Claudins 1 and 7 in the Choroid Plexus.

INTRODUCTION: Uremic rats exhibit elevations of Na/K-ATPase inhibitor Marinobufagenin (MBG). The study investigated whether MBG-induced hypothalamic collagen-1 production occurs in uremic rats. Because choroid plexus cells are involved in transporting substances from the cerebrospinal fluid, the effects of MBG on claudin-1 and claudin-7 were also studied. Whether increased MBG would be associated with plasma procollagen type I C-peptide in patients with chronic kidney disease was also examined. METHODS: Male Sprague-Dawley rats underwent 5/6 nephrectomy. 12 patients with chronic kidney disease undergoing hemodialysis were compared to 6 healthy controls. RESULTS: In the hypothalamus and aorta of rats that underwent 5/6 nephrectomy, uremia was associated with a decrease in Fli1 expression and an increase in collagen 1 production. Consistent with these findings in animals, elevated plasma levels of procollagen type I C-peptide (170±7 ng/ml) in 12 patients with chronic kidney disease undergoing hemodialysis, compared to 6 healthy controls (111±10 ng/ml), were observed. In uremic rats treated with anti-MBG antibodies, Fli1 and collagen 1 expression did not change. Uremic rats develop hypothalamic fibrosis, which was associated with the inhibition of claudin-1 and claudin-7 (50%, P < 0.01 for both) in the choroid plexus of the third ventricle and inhibition of Na/K-ATPase in the brainstem; and administration of anti-MBG antibody prevents these effects. Na/K-ATPase in the brainstem was inhibited by 60% while the Na/K ratio increased. When uremic rats were pretreated with anti-MBG antibody, Na/K-ATPase activity did not change, and the Na/K ratio decreased compared to that of uremic rats. DISCUSSION: The study's data demonstrate that the kidney-brain axis, i.e., activation of peripheral MBG and brain fibrosis, and claudin activation contribute to the pathogenesis of renal failure. CONCLUSION: The main findings of this study are that the CTS (i) affects blood-brain permeability via mechanisms including inhibition of Na/K-ATPase, that (ii) the blood-CSF barrier is regulated by claudins 1 and 7, which are linked to the Na/K ratio in the brain, and (iii) that synthesis of collagen-1 in the hypothalamus comprises a central element in controlling these mechanisms. CKD in rats is associated with central production of collagen-1 and the effect of MBG on brain claudins; antibodies to MBG reverse these pathological changes. These results suggest the importance of the kidneybrain axis in the pathophysiology of kidney diseases.