*3.3. Genetically Induced Models*

In addition to the above-mentioned models for CKD induction, CVD has also been reported in genetic mouse models of CKD. One example is the Alport mouse model, i.e., murine Col4a3 deficiency. The phenotype of C57BL/6 Col4a3 knockout mice was milder than that of 129Sv mice, which correlated with prolonged survival of the C57BL/6 mice. After 20 weeks, the C57BL/6 mice developed CKD associated with functional and structural symptoms of cardiac remodeling [94]. This emphasizes the importance of the genetic background of the mice used in relation to the severity of cardiac disease. For example, C57BL/6 mice usually have much milder phenotypes compared to 129Sv mice.

### **4. Potential Therapeutic Targets of Cardiac Remodeling in CKD**

Reduction or inhibition of LVH might be achieved by non-specific treatments such as reduction of hypervolemia, lowering of blood pressure and treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers that exhibit potential direct e ffects on the myocardium [16,94]. Further strategies to prevent left-ventricular remodeling in patients with mild-to-moderate CKD comprise of reducing overweightness and avoiding hemoglobin concentrations that are too high [98].

Paricalcitol, a vitamin D receptor agonist, has shown a beneficial e ffect on myocardial fibrosis in rats [77,78]. However, in CKD patients, paricalcitol administration failed to improve diastolic function [99,100].

As oxidative stress triggers cardiovascular remodeling, antioxidative therapies have been proposed to protect endothelial cells from reactive oxygen species, thereby preventing endothelial dysfunction. Quercetin and antioxidant enzyme mimetics were shown to inhibit the NFkB pathway and reduce ROS generation in an in vitro assay using endothelial cells [101]. Several studies have attempted to reduce imbalances caused by oxidative stress in cardiac remodeling in CKD. Accordingly, Liu et al. demonstrated that antagonism of the Na/K-ATPase ameliorates uremic cardiomyopathy in 5/6 nephrectomized mice [81,82]. Na/K-ATPase activation leads to increased ROS production and acts as a signal transducer inside cardiomyocytes [81]. In activated Na/K-ATPase signaling, microRNA 29b-3b is downregulated, and thus fails to inhibit collagen expression, which has been shown in cardiac fibroblasts [81,83]. Na/K-ATPase is also known to stimulate mTOR signaling, thereby activating pro-fibrotic pathways. Moreover, the mTOR inhibitor rapamycin has been shown to inhibit cardiac fibrosis in rats [102].

As some of the uremic toxins are derived from intestinal bacteria, the microbiome could be another potential target in the cardiorenal syndrome. Thus, indoxyl sulfate and para-Cresyl sulfate serum

levels were reduced by antibiotic therapy in ESRD patients [103,104]. Indoxyl sulfate binds to the cannabinoid receptor [75]. Interestingly, inhibition of this receptor has also been shown to reduce cardiac fibrosis in 5/6 nephrectomized mice [75].

FGF23 promotes cardiac fibrosis and LVH. Additionally, FGF23 signaling in the liver causes the production of inflammatory cytokines. In the bone, FGF23 inhibits mineralization, leading to increased circulating phosphorus levels and a reduction in the production of EPO [64,75]. Thus, the identification of FGF23 receptors in the respective organs will be crucial in future research since their selective blockade could be considered as a therapeutic target [64]. On the other hand, FGF23 antibody treatment caused mineral disturbances, in particular hyperphosphatemia and was associated with increased mortality in a CKD rat model [105]. Recombinant Klotho was used in an experimental mouse model to attenuate cardiac remodeling and reduce cardiac and renal fibrosis [105,106]. A positive correlation between FGF23 and cardiac hypertrophy exists in a Klotho-deficient state, but not in a Klotho-repleted state [76,105,106]. In addition, pharmacological interference with cardiac FGF23/FGFR4 signaling might have a protective effect on CKD- and age-related LVH [68]. First studies in rats report that pharmacological inhibition of FGFR might be a potent blood pressure-independent mechanism to prevent LVH in CKD [59].

CKD patients have low EPO levels, which are associated with cardiac fibrosis. A study in 5/6 nephrectomized rats showed that EPO in combination with enalapril reduced cardiac fibrosis and capillary rarefaction. The underlying mechanisms are likely multifactorial but may encompass decreased myocardial oxidative stress [81]. In CKD patients, there is better survival in those treated with EPO to a hemoglobin level of 10-12 g/dl, whereas normalization of hemoglobin levels was not beneficial [80,107].

Calò et al. identified rho kinase (ROCK) activation as a potential LVH marker in CKD patients, which indicates that inhibition of ROCK activation might serve as a target to treat cardiac remodeling in those patients [108].

A study performed in 5/6 nephrectomized rats treated with the PPARα agonist clofibrate did indeed reveal improved cardiac function and prevention of LVH [84].

Finally, restoring kidney function can at least partially reverse cardiac changes. It has been shown by echocardiography that a kidney transplantation improves left-ventricular function [103].

In conclusion, to date, few specific therapies exist that can inhibit cardiac remodeling in CKD. A better understanding of the cell types involved and their mechanisms of activation, e.g., by crosstalk or presumed uremic toxins, will guide the development of urgently needed novel therapeutics.

**Author Contributions:** A.B. and N.K. drafted the manuscript and contributed equally. J.F. and R.K. revised the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by Deutsche Forschungsgemeinschaft Grant SFB/TRR 219.

**Conflicts of Interest:** The authors declare no conflict of interest.
