Fig. 4.
Risk factors for uremic cardiomyopathy and proposed mechanisms of attenuation of pathological cardiac remodeling by αKlotho. αKlotho deficiency is a novel risk factor for uremic cardiomyopathy. Soluble αKlotho deficiency is an intermediate mediator of the pathological cardiac remodeling observed in CKD. Experimental αKlotho overexpression (Tg-Kl) suppressed phosphorylation of Smad2/3 and Erk, which are known to be involved in uremic cardiac fibrosis. Furthermore, αKlotho may protect the heart against stress-induced cardiac hypertrophy by inhibiting TRPC-6 channel-mediated abnormal Ca2+ signaling in the heart or against uremic solute indoxyl sulfate-induced myocardial hypertrophy probably by suppressing NADPH oxidase Nox2/Nox4-derived reactive oxygen species production and its downstream signaling. CHF, congestive heart failure; Erk, extracellular signal-regulated kinase; LVH, left ventricular hypertrophy; MAPK, mitogen-activated protein kinases; Nox, NADPH oxidase; SCD, sudden cardiac death; TRPC-6, transient receptor potential canonical-6.