**3. Conclusion**

were impaired in all mutant ECs. Similarly, altered eNOS activation and low insulin action have recently been demonstrated in the endothelium of patients with diabetes mellitus [36]. Thus, impaired insulin delivery to ECs may lead to defective NOS and eNOS activation in PKR1ec‐/‐ aortas, consequently impairing endothelium‐dependent relaxation. These data

PKR1 signaling also contributes to heart development. In developing heart, PKR1 regulates epicardial‐mesenchymal transition (EMT) to form epicardial‐derived progenitor cell (EPDC) [38]. Genetic ablation of PKR1 in epicardium leads to ventricular hypoplasia and septal defects during embryogenesis. Impaired vasculogenesis in these mice is due to impaired EPDC proliferation as well as a defective EPDC differentiation into endothelial and smooth muscle cell type. PKR1 in EPDCS activates Akt signaling, changes cell morphology, actin cytoskeleton remodeling and EMT gene expression profile. Epicardial‐PKR1 contributes to cardiomyocyte,

Global PKR1‐knockout mice have peripheral obesity accompanied by a diabetes‐like syn‐ drome at the late ages (36 weeks old) [7], mainly due to endothelial dysfunction and impaired adipose tissue functions [37]. These mice also exhibited cardiomegaly, severe interstitial fibrosis and cardiac dysfunction under the stress conditions. These mice also displayed impaired renal tubular dilation, reduced glomerular capillaries, urinary phosphate excretion

Similarly, endothelial‐specific PKR1‐knockout mice (PKR1ec‐/‐) also displayed dilatation of Bowman's spaces in most glomeruli, a compact glomerulus, fibrosis and enlarged tubular structures with a swollen necrotic nucleus, abnormal mitochondria and aberrant organization of podocytes. Abnormal tubular function with higher levels of absolute renal phosphate (Pi) excretion in the PKR1ec‐/‐ mice is due to lower levels of sodium‐calcium and sodium phosphate exchanger. The morphological changes in the PKR1ec‐/‐ kidneys were associated with higher levels of apoptosis and impaired insulin signaling and lipid accumulation. Mutant mice displayed high levels of creatinine clearance and proteinuria. [34] Endothelial dysfunction resulted from loss of PKR1 signaling partially underlies the pathological features of heart and

PKR1 signaling in kidney is essential for nephron development during embryogenesis [38]. Recently, it has been shown that mutant mice with targeted PKR1 gene disruptions in nephron progenitors exhibited partial embryonic and postnatal lethality due to hypoplastic kidneys with premature glomeruli and necrotic nephrons. Kidney developmental defects in these mice are manifested in the adult stage as renal atrophy with glomerular defects, nephropathy and uremia. Thus, PKR1 is necessary for renal mesenchymal‐epithelial transition (MET) that is involved in the formation of renal progenitors, regulating glomerulogenesis toward forming nephrons during kidney development. Indeed, PKR1 through NFATc3 modifies MET proc‐

highlight the role of PKR1 as a positive regulator of insulin uptake [37].

proliferation and rhythmicity in a paracrine pathway.

120 Adiposity - Omics and Molecular Understanding

**2.5. Prokineticin in renal development and function**

and proteinuria [34].

kidney.

essing to the development of nephron.

PKR1 signaling has various beneficial effects, e.g., central regulation of appetite, the sup‐ pression of adipocyte mass and insulin‐sensitizing effects on skeletal muscle and other tissues, cardiac regenerative effects and regulation of kidney function. This has attracted considerable interest in the possible use of this receptor as a target for treatments combating obesity, diabetes and cardiovascular diseases. Intracardiac PKR1 gene transfer improved survival rate and heart functions after myocardial infarction [33]. Since PKR2 has been found to contribute to vascular leakage and hypertrophic cardiomyopathy [39], several laboratories are focused on the discovery of PKR1 agonist. Recently, PKR1 non‐peptide agonist has been identified [40]. PKR1 agonist prevents cardiac lesion formation and improved cardiac function after myocardial infarction in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis*.* PKR1 agonist in treatment strategies of metabolic disease remains to be studied.

How prokineticin‐2 contributes to the AT remodeling [41], how it modulates the interaction between the adipocytes, macrophages and endothelial cells to regulate AT expansion [42] remains also to be determined. Circulating prokineticin levels in obese, diabetic and heart failure patients remain to be explored.
