Figure 1.

Complementary interplay of “cascades of injury.” Fibroblast growth factor (FGF)23/Klotho–renin–angiotensin–aldosterone system–mineralocorticoid receptor and their interrelationships. Both angiotensin II and aldosterone directly stimulate FGF23 secretion. In chronic kidney disease, (right) Klotho insufficiency and (middle) mineralocorticoid receptor activation act on different cell types and through multipronged and complementary systemic and local molecular and signaling mechanisms to promote cardiorenal injury. As detailed in the text, both (broad green vertical band on the right) Klotho reactivation and/or Klotho supplementation and (broad green vertical band on the left) mineralocorticoid receptor antagonist administration may potentially prevent and attenuate these numerous cardiorenal injury–promoting cascades. For additional information, see a very recent review by the author that details in depth the expansive array of intersections and interplays of the 3 cascades of injury.³³ ACE, angiotensin-converting enzyme.