The lack of an appropriate animal model that spontaneously develops diabetic nephropathy has been a significant limitation in the search for genetic factors underlying this disease and the development of new therapeutic strategies to prevent progressive renal disease in diabetes. We introgressed the mitochondria and some passenger loci from the FHH/EurMcwi rat into the genetic background of diabetic GK rats, creating a new rat strain, T2DN (T2DN/Mcwi). Despite the high degree of genetic similarity between T2DN and GK rats (97% at 681 loci), diabetes ensues earlier and progresses more severely in T2DN rats. T2DN rats exhibit proteinuria by 6 months of age, accompanied by renal histologic abnormalities such as focal glomerulosclerosis, mesangial matrix expansion, and thickening of basement membranes. These characteristics progress over time, and nearly all T2DN rats exhibit diffuse global glomerulosclerosis with nodule formation and arteriolar hyalinosis by 18 months of age. The histologic changes in the kidney of T2DN rats closely mimic the changes seen in the kidney of patients with diabetes. These results indicate that the T2DN rat is a suitable model for investigating diabetic nephropathy. Here we report the initial genetic and physiological characterization of this new rat model of diabetic nephropathy. Diabetes 53: [735][736][737][738][739][740][741][742] 2004 O ne of the major morbidity and mortality factors confronted by patients with diabetes is an increased risk of developing diabetic nephropathy that often progresses to end-stage renal disease (ESRD) (1-3). A long-standing question pertaining to the development of renal disease in diabetes concerns the mechanisms involved in this process. A wealth of data have been generated on possible mechanisms by which diabetes and its ancillary metabolic, hemodynamic, growth, and glomerular cell injury-related alterations may modulate the progression of diabetic nephropathy (4 -7). Nevertheless, the observation that approximately two-thirds of patients with diabetes do not develop renal disease indicates that hyperglycemia is a permissive factor in diabetic nephropathy, but elevated plasma glucose levels alone do not fully account for renal injury (1). Thus, genetic factors are thought to play an important role in the susceptibility for diabetic nephropathy, with several clinical and epidemiologic studies supporting this hypothesis (8 -10).The complex interplay between diabetes-dependent and -independent factors in determining the progression of renal disease could become more amenable to study if there were adequate animal models that spontaneously develop diabetes and renal lesions that mimic those seen in patients with diabetic nephropathy. However, to date, no rodent model of diabetes that fully recapitulates the chronology of events and histologic changes in the kidney that are characteristic of patients with diabetic nephropathy has been developed. Several rodent models of spontaneous diabetes, such as the Zucker rat, BB rat, and DB mice, exhibit glomerula...

quence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains. Am J Physiol Cell Physiol 291: C1183-C1192, 2006. First published July 19, 2006 doi:10.1152/ajpcell.00234.2006.-Rat remains a major biomedical model system for common, complex diseases. The rat continues to gain importance as a model system with the completion of its full genomic sequence. Although the genomic sequence has generated much interest, only three complete sequences of the rat mitochondria exist. Therefore, to increase the knowledge of the rat genome, the entire mitochondrial genomes (16,307-16,315 bp) from 10 inbred rat strains (that are standard laboratory models around the world) and 2 wild rat strains were sequenced. We observed a total of 195 polymorphisms, 32 of which created an amino acid change (nonsynonymous substitutions) in 12 of the 13 protein coding genes within the mitochondrial genome. There were 11 single nucleotide polymorphisms within the tRNA genes, six in the 12S rRNA, and 12 in the 16S rRNA including 3 insertions/deletions. We found 14 single nucleotide polymorphisms and 2 insertion/deletion polymorphisms in the D-loop. The inbred rat strains cluster phylogenetically into three distinct groups. The wild rat from Tokyo grouped closely with five inbred strains in the phylogeny, whereas the wild rat from Milwaukee was not closely related to any inbred strain. These data will enable investigators to rapidly assess the potential impact of the mitochondria in these rats on the physiology and the pathophysiology of phenotypes studied in these strains. Moreover, these data provide information that may be useful as new animal models, which result in novel combinations of nuclear and mitochondrial genomes, are developed. genome; mitochondria MITOCHONDRIA ARE THE ONLY organelles (other than the nucleus) with their own DNA, which is maternally inherited (31, 36). The mammalian mitochondrial DNA (mtDNA) is a circular, double-stranded DNA that lacks introns and has only ϳ7% noncoding sequences (23) in contrast to the genomic DNA. The mtDNA encodes 37 genes, including 13 protein-coding genes that, in conjunction with subunits encoded by the nuclear genome, form the electron transport chain, the primary ATP producer for the cell. Also included within these 37 coding genes are 22 tRNA genes whose function is to transport amino acids to the ribosome and match them to the codons of the mRNAs thus facilitating incorporation of amino acids into the growing polypeptide during translation. The final 2 genes are rRNA genes. The D-loop or control region, although noncoding, contains binding sites for two transcription factors, three conserved sequence blocks (CSBs) associated with initiation of replication and the loop strand termination associated sequences (9,21,23,61

Our aim was to investigate the effects of the negative pressure reflex on mechanically opposing pharyngeal muscles during wakefulness, slow-wave sleep (SWS), and rapid eye movement (REM) sleep. In four goats with isolated upper airways, we measured tracheal airflow and electrical activity of the thyropharyngeus (TP; constricting), the stylopharyngeus (SP; dilating), and the diaphragm (Dia). In the wakefulness state in response to negative pressure tests, TP decreased (65%), SP increased (198%), and tidal volume (VT) (66%) and rate of rise of Dia (Dia(slope), 69%) decreased (P < 0.02). Similarly, during SWS, the negative pressure response of TP (31%), VT (61%), and Dia(slope) (60%) decreased, whereas SP (113%) increased, relative to SWS control (P < 0.02). In REM sleep, the negative pressure response by TP and SP were small, whereas both VT (38%) and Dia(slope) (24%) were greatly decreased (P < 0.02) compared with REM control. Inspiratory duration remained unchanged in response to negative pressure tests in all states. These data provide evidence that mechanically opposing inspiratory and expiratory pharyngeal muscles are reciprocally controlled and their response to negative pressure are state dependent.

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