Citrin is the liver-type mitochondrial aspartate-glutamate carrier that participates in urea, protein, and nucleotide biosynthetic pathways by supplying aspartate from mitochondria to the cytosol.Citrin also plays a role in transporting cytosolic NADH reducing equivalents into mitochondria as a component of the malate-aspartate shuttle. In humans, loss-of-function mutations in the SLC25A13 gene encoding citrin cause both adult-onset type II citrullinemia and neonatal intrahepatic cholestasis, collectively referred to as human citrin deficiency. Citrin knock-out mice fail to display features of human citrin deficiency. Based on the hypothesis that an enhanced glycerol phosphate shuttle activity may be compensating for the loss of citrin function in the mouse, we have generated mice with a combined disruption of the genes for citrin and mitochondrial glycerol 3-phosphate dehydrogenase. The resulting double knock-out mice demonstrated citrullinemia, hyperammonemia that was further elevated by oral sucrose administration, hypoglycemia, and a fatty liver, all features of human citrin deficiency. An increased hepatic lactate/pyruvate ratio in the double knock-out mice compared with controls was also further elevated by the oral sucrose administration, suggesting that an altered cytosolic NADH/NAD ؉ ratio is closely associated with the hyperammonemia observed. Microarray analyses identified over 100 genes that were differentially expressed in the double knock-out mice compared with wild-type controls, revealing genes potentially involved in compensatory or downstream effects of the combined mutations. Together, our data indicate that the more severe phenotype present in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice represents a more accurate model of human citrin deficiency than citrin knock-out mice.

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Abstract. Leukemia inhibitory factor (LIF) is known to play a crucial role in the conversion of mesenchyme into epithelium during nephrogenesis. This study was carried out to test the hypothesis that LIF and LIF receptor (LIFR) are involved in the renal epithelial regeneration after acute renal failure. First, the authors investigated the spatiotemporal expression of LIF and LIFR in fetal and adult rat kidney. In developing kidney, LIF was expressed in the ureteric buds and LIFR was located in nephrogenic mesenchyme and the ureteric buds; in adult kidney, LIF and LIFR expression was confined to the collecting ducts. Next, the authors examined the expression of LIF and LIFR during the recovery phase after ischemia-reperfusion injury. Real-time PCR analysis revealed that LIF mRNA expression was significantly increased from day 1 to day 7 after reperfusion and that LIFR mRNA was upregulated from day 4 to day 14. Histologic analysis demonstrated that the increased expression of LIF mRNA and protein was most marked in the outer medulla, especially in the S3 segment of the proximal tubules. To elucidate the mitogenic role of LIF in the regeneration process, cultured rat renal epithelial (NRK 52E) cells were subjected to ATP depletion (an in vitro model of acute renal failure), and LIF expression was found to be enhanced during recovery after ATP depletion. Blockade of endogenous LIF with a neutralizing antibody significantly reduced the cell number and DNA synthesis during the recovery period. These results suggest that LIF participates in the regeneration process after tubular injury.

Blockade of the renin-angiotensin system has been established as a treatment for heart failure with hypertension and left ventricular hypertrophy, and for progressive kidney diseases. The present study was con-