Positron emission tomography imaging of renal mitochondria is a powerful tool in the study of acute and progressive kidney disease models.

Mitochondrial dysfunction plays a critical role in the pathogenesis of kidney diseases via ATP depletion and reactive oxygen species overproduction. Nonetheless, few studies have reported the renal mitochondrial status clinical settings, partly due to a paucity of methodologies. Recently, a positron emission tomography probe, 18F-BCPP-BF, was developed to non-invasively visualize and quantitate the renal mitochondrial status in vivo. Here, 18F-BCPP-BF positron emission tomography was applied to three mechanistic kidney disease models in rats: kidney ischemia-reperfusion, 5/6 nephrectomy and anti-glomerular basement membrane glomerulonephritis. In rats with ischemia-reperfusion, a slight decrease in the kidney uptake of 18F-BCPP-BF was accompanied by morphological abnormality of the mitochondria in the proximal tubular cells after three hours of reperfusion, when the kidney function was slightly declined. In 5/6 nephrectomy and rats with anti-glomerular basement membrane glomerulonephritis, the kidney uptake of 18F-BCPP-BF cumulatively decreased with impairment of the kidney function, which was accompanied by a reduction of mitochondrial protein and a pathological tubulointerstitial exacerbation rather than glomerular injury. The 18F-BCPP-BF uptake in the injured kidney was suggested to represent the volume of healthy tubular epithelial cells with normally functioning mitochondria. Thus, this positron emission tomography probe can be a powerful tool for studying the pathophysiological meanings of the mitochondrial status in kidney disease.

A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro.

Cinacalcet hydrochloride (cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral calcimimetic agent, with a wider safety margin.

Identification of SMEK2 as a candidate gene for regulation of responsiveness to dietary cholesterol in rats.

We have previously mapped a diet-induced hypercholesterolemia locus (Dihc2) to chromosome 14 in the F2 generation cross of high-responsive exogenous hypercholesterolemia rats and low-responsive BN rats. To identify a causal gene within this locus, we constructed interval-specific congenic lines and carried out expression and sequencing analyses. Here we narrowed Dihc2 to a region including 33 genes and predicted transcripts and identified RGD1309450_predicted, a homologous gene of SMEK2, as a strong candidate for responsiveness to dietary cholesterol. Our finding provides new insights into the pathway underlying the individual responsiveness to dietary cholesterol in vivo.