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

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 and proteinuria [34].

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 kidney.

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‐ essing to the development of nephron.
