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.