Figure 9.

Schematic showing opposite effects on hemodynamic response induced by paracrine FGF activation of FGFR1 in the renal distal tubule (DT) and FGF-23 activation of FGFR1/α-Klotho. (A) Novel scenario showing that paracrine FGF ligands released locally in the kidney, possibly from the glomerulus and/or renal tubules, in response to yet-to-be-defined stimuli (such as changes in hemodynamics or solute delivery) activate FGFR1, independently of α-Klotho, likely in the DT, leading to decreased tubular Na reabsorption (downregulation of NKCC2 expression), increased Ace2 expression that degrades Ang II, and elevated circulating sKl levels that alter TRPC6 expression in the heart. The cardioprotective effects could be due to reductions in BP via effects on Na reabsorption and Ace2 or through effects of sKl to regulate TRPC6 in the heart. (B) FGF-23 activates canonic FGFR1/α-Klotho complexes in the DT to increase NCC-dependent Na reabsorption, and to decrease Ace2 and sKI, leading to hypertension and LVH. FGF-23 is also purported to have direct effects on FGFR4 in the heart to stimulate LVH. The molecular mechanisms mediating the opposite cardiovascular effects of FGFR1 activation in the kidney by paracrine FGF ligands and activating FGFR1 antibodies (cardioprotective) and FGF-23 activation of FGFR/α-Klotho complexes in the kidney (cardiotoxic) remain to be defined.