The remnant kidney model in C57BL6 mice does not develop progressive chronic kidney disease (CKD). In this study we modified the model to mimic features of human CKD and to define accelerants of disease progression using three strains of mice. Following the procedure there was a progressive increase in albuminuria, progressive loss in renal function, severe glomerulosclerosis and interstitial fibrosis, hypertension, cardiac fibrosis, and anemia by 4 weeks in CD-1 mice and by 12 weeks in 129S3 mice. In contrast, even after 16 weeks, the C57BL/6 mice with a remnant kidney had modestly increased albuminuria without increased blood pressure and without developing CKD or cardiac fibrosis. The baseline blood pressure, determined by radiotelemetry in conscious animals, correlated with CKD progression rates in each strain. Administering angiotensin II overcame the resistance of C57BL/6 mice to CKD following renal mass reduction displaying high blood pressure and albuminuria, severe glomerulosclerosis, and loss of renal function by 4 weeks. Decreasing blood pressure with olmesartan but not hydralazine in CD-1 mice with a remnant kidney reduced CKD progression and cardiac fibrosis. C57BL/6 mice with a remnant kidney and DOCA-salt hypertension developed modest CKD. Each strain had similar degrees of interstitial fibrosis in three different normotensive models of renal fibrosis. Thus reducing renal mass in CD-1 or 129S3 mice mimics many features of human CKD. Angiotensin II can convert the C57BL/6 strain from CKD-resistant to susceptible in this disease model.

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Although ghrelin has been demonstrated to stimulate energy intake and storage through a central mechanism, its effect on hepatic lipid metabolism remains largely uncharacterized. Ghrelin receptor antagonism or gene deletion significantly decreased obesity-associated hepatic steatosis by suppression of de novo lipogenesis, whereas exogenous ghrelin stimulated lipogenesis, leading to hepatic lipid accumulation in mice. The effects of ghrelin were mediated by direct activation of its receptor on hepatocytes. Cultured hepatocytes responded to ghrelin with increased lipid content and expression of lipogenesis-related genes. Ghrelin increased phosphorylation of S6, the downstream target of mammalian target of rapamycin (mTOR) signaling in cultured hepatocytes, whereas ghrelin receptor antagonism reduced hepatic phosphorylation of S6 in db/db mice. Inhibition of mTOR signaling by rapamycin markedly attenuated ghrelin-induced up-regulation of lipogenesis in hepatocytes, whereas activation of hepatic mTOR signaling by deletion of TSC1 increased hepatic lipogenesis. By interacting with peroxisome proliferator-activated receptor-γ (PPARγ), mTOR mediates the ghrelin-induced up-regulation of lipogenesis in hepatocytes. The stimulatory effect of ghrelin on hepatic lipogenesis was significantly attenuated by PPARγ antagonism in cultured hepatocytes and in PPARγ gene-deficient mice. Our study indicates that ghrelin activates its receptor on hepatocytes to promote lipogenesis via a mechanism involving the mTOR-PPARγ signaling pathway.NAFLD | gastric hormone | growth hormone secretagogue receptor | GHSR T riglyceride deposition in the liver, which is strongly associated with obesity, is the initial event in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Over time, hepatic steatosis may progress to steatohepatitis, cirrhosis, and primary hepatocellular carcinoma (1). The current therapeutic strategy for NAFLD has been focused on reversal of hepatic steatosis, primarily through weight reduction. Treatment is often ineffective because of the difficulty in achieving sustained weight loss. Alternative approaches are needed but are limited by incomplete understanding of the mechanisms controlling the development of steatosis. Gastric hormones may be involved in regulation of lipid metabolism. Studies in both animals and humans demonstrate that ghrelin, a 28-aa peptide hormone secreted by X/A-like endocrine cells in the gastric fundus (2, 3), stimulates lipid accumulation in adipose tissue (4). Chronic infusion of ghrelin increases both adipose and hepatic lipid storage (5). Genetic disruption of either ghrelin or ghrelin receptor genes renders mice resistant to obesity and to the development of hepatic steatosis (6). Interestingly, the anabolic effect of ghrelin appears to be independent of its hyperphagic action. Chronic third intracerebroventricular infusion of ghrelin in diet-induced obese rats increases adiposity and gene expression of lipogenic enzymes in white adipose tissue while food intake remains unchanged (7)....