*3.6. Cardiorenal Syndrome*

Cardiorenal syndromes have been defined as "disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other [36]. There are five subcategories of cardiorenal syndrome based on the primary damaged organ (heart or kidney) and the time course of progression (acute or chronic) [36]. Type 2 cardiorenal syndrome (CRS2) is where HF causes renal dysfunction, and type 4 CRS (CRS4) is where advanced CKD promotes heart dysfunction.

With respect to CRS4, clinical reports have substantiated a relationship between heart and kidney disease [37]. It appears that Klotho deficiency may contribute to the generation of cardiac hypertrophy observed in patients CKD stages G3a–b and G4; however, publications on this issue are limited [38].

In the case of CRS2, a study on a mice model of HF has shed light on the potential mechanisms connecting cardiac and renal dysfunction [39]. In these mice, the constriction of the aorta induced LVH and HF. The increased cardiac remodeling was associated with a significant reduction of Klotho and activation of the Wnt/β-catenin and renin–angiotensin system (RAS). The Wnt/β-catenin activation mediates the injury in both organs, heart, and kidney. Once HF is established, the renal expression of podocalyxin was reduced while fibronectin and Snail1 expression increased, resulting in kidney interstitial fibrosis and albuminuria [39].

Furthermore, di fferent cardiac Wnt ligands increased together with β-catenin, angiotensinconverting enzyme (ACE), renin, and angiotensin I (AT1) expression. Perhaps, the most important finding of this research is that the inhibition of the cardiac-secreted Wnt/β-catenin/RAS axis prevented kidney injury by a downregulation of the expression of fibronectin, Snail1, ACE, renin, and AT1 in the kidney with a consequent reduction of kidney interstitial fibrosis. All the cardiac lesions worsened

in association with renal-dependent Klotho depletion. The presence of sKlotho partially inhibited Wnt/β-catenin signaling, which in turn promoted the downregulation of cardiac fibronectin and α-smooth muscle actin. Therefore, the activity of Wnt/β-catenin in the heart is accompanied by kidney injury. Concomitantly, Klotho deficiency resulting from kidney failure worsens cardiac remodeling and function. This finding is not surprising since Klotho deficiency, high serum phosphate, and elevated FGF23 have been demonstrated to modulate cardiac remodeling [40] (Figure 2).

In CKD patients, more information on the relationship between serum Klotho and FGF23 levels and the values of the Wnt ligands, such as Wnt1, Wnt3a, or Wnt10b, could be useful to assess the comorbidities dependent on the Wnt signaling system, such as renal and cardiac fibrosis.

## **4. FGF23**/**Klotho**/**Wnt in Cardiovascular Disease (CVD)**

The involvement of Wnt signaling activation in the pathogenesis of CVD has been widely documented. In addition to the cardiovascular development during embryogenesis, Wnt signaling participates in many cardiac and vascular pathological processes such as RAS alterations, cardiac fibrosis and hypertrophy, atherosclerosis, vascular calcification, endothelial dysfunction, myocardial infarction, or arrhythmias [41] (Figure 2).
