*2.10. Uremic Toxins*

The role of uremic toxins in the development of cardiac remodeling is less well established. Recent work sheds light on the potential roles of asymmetric dimethylarginine (ADMA), advanced glycation end-products (AGE), trimethylamine N-oxide (TMAO) and indoxyl sulfate [69]. ADMA has been reported to be involved in regulation of nitric oxide, reactive oxygen species and renal anemia [69,70]. The AGE/RAGE axis is responsible for cell damage in CVD [69], driving cardiac fibrosis. TMAO, a metabolite derived from choline, is linked with left-ventricular diastolic dysfunction [71] and cardiac fibrosis [69].

In addition, several other uremic toxins are also thought to promote the cardiorenal syndrome by direct cardiotoxicity, including indoxyl sulfate and p-cresyl sulfate [71,72]. Indoxyl sulfate is a product of the intestinal catabolism of tryptophan with insu fficient dialytic removal, as it is bound to albumin in the blood. In uremia, it increases up to 88-fold [73] and has been shown to mediate immune dysfunction and cytotoxic e ffects on endothelial cells in patients with end-stage renal disease [74]. Indoxyl sulfate stimulates the cannabinoid receptor type 1 and was associated with fibrotic e ffects via modulation of Akt signaling in myofibroblasts [75].


**Table 1.** Some systemic factors that have been reported to be involved in uremic cardiomyopathy.

Several studies have pointed towards a role of uremic toxins in cardiac remodeling, however, the complex mechanisms of cell-type activation that drive cardiac fibrosis, hypertrophy and capillary loss are still unclear. Further studies using state-of-the-art single-cell technologies may shed more light on this important disease that affects numerous CKD/ESRD patients.

### **3. Mouse Models of Cardiac Remodeling in CKD**

To date, most animal studies investigating mechanisms and interventions in the cardiorenal syndrome have been performed in rats. The models employed (5/6 nephrectomy, adenine nephropathy, ischemia reperfusion injury, etc.) are well established and cause reliable cardiac remodeling. However, mouse models do offer some advantages, the most important of which is the possibility of generating genetic modifications, which enable the analysis of specific pathways and molecular mechanisms. Thus, improving mouse models of CKD-CVD is one important goal in order to clarify the pathogenesis of the cardiorenal syndrome and develop novel therapies for patients. Several attempts have been made to establish CKD-CVD in mice. They can be divided into three approaches: surgical interventions, chemical interventions and genetic interventions. Table 2 summarizes the kidney parameters and functional and structural cardiac parameters of murine CKD-CVD studies.



*Toxins* **2020**, *12*, 161
