Klotho & Activin A in kidney injury Plasma Klotho is maintained in unilateral obstruction despite no upregulation of Klotho biosynthesis in contralateral kidney

In a new paradigm of etiology related to Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) kidney injury may cause induction of factors in the injured kidney that are released into the circulation and thereby initiate and maintain renal fibrosis and CKD-MBD. Klotho is believed to ameliorate renal fibrosis and CKD-MBD, while ActivinA might have detrimental effects. The unilateral ureter obstruction (UUO) model is used here to examine this concept by investigating early changes related to renal fibrosis in obstructed kidney, untouched contralateral kidney and vasculature, which might be affected by secreted factors from the obstructed kidney, and compared to unilateral nephrectomized controls (UNX). Obstructed kidneys showed early Klotho gene- and protein depletion, whereas p-Klotho increased in both UUO-and UNX rats. Contralateral kidneys had no compensatory upregulation of Klotho and maintained normal expression of fibrosis-related genes, as did remnant UNX kidneys. These findings indicate that contralateral kidneys are protected from fibrosis, presumably due to preserved Klotho levels. Additionally, UUO caused upregulation of TGF-β and induction of Periostin and ActivinA in obstructed kidneys without changes in the contralateral. Plasma ActivinA doubled in UUO rats after 10days while no changes were seen in UNX rats suggesting secretion of ActivinA from the obstructed kidney with potentially systemic effects on CKD-MBD. As such, increased aortic Sclerostin was observed in UUO rats compared to UNX and normal controls. The present results are in line with the new paradigm and show very early vascular effects of unilateral kidney fibrosis supporting existence of a new kidney-vasculature axis.