Renal autoregulation is impaired in early (1 wk) diabetes mellitus (DM) induced by streptozotocin, but effective in established DM (4 wk). Furthermore nitric oxide synthesis (NOS) inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) significantly improved autoregulation in early DM but not in established DM. We hypothesized that autoregulation is transiently impaired in early DM because of increased NO availability in the kidney. Because of the conflicting evidence available for a role of NO in DM, we tested the hypothesis that DM reduces autoregulation effectiveness by reducing the spatial similarity of autoregulation. Male Long-Evans rats were divided into control (CON) and diabetic (DM; streptozotocin) groups and followed for either 1 wk (CON1, n = 6; DM1, n = 5) or 4 wk (CON4, n = 7; DM4, n = 7). At the end of the experiment, dynamic autoregulation was assessed in isoflurane-anesthetized rats by whole kidney RBF during baseline, NOS1 inhibition, and nonselective NOS inhibition. Kidney surface perfusion, monitored with laser speckle contrast imaging, was used to assess spatial heterogeneity of autoregulation. Autoregulation was significantly impaired in DM1 rats and not impaired in DM4 rats. L-NAME caused strong renal vasoconstriction in all rats, but did not significantly affect autoregulation dynamics. Autoregulation was more spatially heterogeneous in DM1, but not DM4. Therefore, our results, which are consistent with transient impairment of autoregulation in DM, argue against the hypothesis that this impairment is NO-dependent, and suggest that spatial properties of autoregulation may also contribute to reduced autoregulatory effectiveness in DM1.
Ellis-van Creveld (EVC) syndrome is an autosomal recessive chondrodysplasia. The affected individuals bear a series of skeleton defects, congenital heart septum anomalies, midfacial defects, and dental defects. Previous studies using Evc or Evc2 mutant mice have characterized the pathological mechanism leading to various types of congenital defects. Some patients with EVC have supernumerary tooth; however, it is not known yet if there are supernumerary tooth formed in Evc or Evc2 mutant mice, and if yes, what is the pathological mechanism associated. In the present study, we used Evc2 mutant mice and analyze the pattern of molars in Evc2 mutant mice at various stages. Our studies demonstrate that Evc2 loss of function within the dental mesenchymal cells leads to abnormal molar patterning, and that the most anterior molar in the Evc2 mutant mandible represents a supernumerary tooth. Finally, we provide evidence supporting the idea that both compromised Hedgehog signaling and elevated WNT signaling due to Evc2 loss of function contributes to the supernumerary tooth formation.
Diabetes is a leading cause of chronic kidney disease and increases susceptibility to blood pressure induced glomerular injury. Autoregulation is the only mechanism that protects the glomeruli when blood pressure fluctuates. Impaired autoregulation has been reported in early DM and attributed to increased nitric oxide (NO) but intact autoregulation has been demonstrated in established DM. We hypothesized that intrarenal NO increases in early DM with corresponding impairment of autoregulation and that neuronal NOS (nNOS) contributes to the increased NO. Male Long‐Evans rats were divided into two groups: one week diabetic (N=5) and one week intact (N=3). Diabetes was induced with streptozotocin (60mg/kg i.v.) and depot insulin was used to keep blood glucose ~20–24 mmol/L. Rats were anaesthetized (isoflurane) and their left kidneys were exposed. Renal perfusion pressure was forced with a servo‐controlled aortic occluder and the resulting renal blood flow was measured with an ultrasound flow probe during control, nNOS inhibition (L‐VNIO) and non selective NOS inhibition (L‐NAME). Renal autoregulation was intact in all animals except one intact animal. nNOS protein distribution was similar and was little response to either NOS inhibitor in all rats. We conclude that renal autoregulation is not impaired, and that intrarenal NO does not play a role in early diabetes in these rats. Supported by CIHR MOP‐102694.
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