Stoessel A, Himmerkus N, Bleich M, Bachmann S, Theilig F. Connexin 37 is localized in renal epithelia and responds to changes in dietary salt intake.

Deficiency of nitric oxide (NO) represents a consistent manifestation of endothelial dysfunction (ECD), and the accumulation of asymmetric dimethylarginine occurs early in renal disease. Here, we confirmed in vitro and in vivo the previous finding that a fragment of collagen XVIII, endostatin, was upregulated by chronic inhibition of NO production and sought to support a hypothesis that primary ECD contributes to nephrosclerosis in the absence of other profibrotic factors. To emulate more closely the indolent course of ECD, the study was expanded to an in vivo model with N(G)-monomethyl-L-arginine (L-NMMA; mimics effects of asymmetric dimethylarginine) administered to mice in the drinking water at subpressor doses of 0.3 and 0.8 mg/ml for 3-6 mo. This resulted in subtle but significant morphological alterations detected in kidneys of mice chronically treated with L-NMMA: 1) consistent perivascular expansion of interstitial matrix components at the inner stripe of the outer medulla and 2) collagen XVIII/endostatin abundance. Ultrastructural abnormalities were detected in L-NMMA-treated mice: 1) increased activity of the interstitial fibroblasts; 2) occasional detachment of endothelial cells from the basement membrane; 3) splitting of the vascular basement membrane; 4) focal fibrosis; and 5) accumulation of lipofuscin by interstitial fibroblasts. Preembedding labeling of microvasculature with anti-CD31 antibodies showed infiltrating leukocytes and agglomerating platelets attaching to the visibly intact or denuded capillaries. Collectively, the data indicate that the mouse model of subpressor chronic administration of L-NMMA is not a robust one (endothelial pathology visible only ultrastructurally), and yet it closely resembles the natural progression of endothelial dysfunction, microvascular abnormalities, and associated tubulointerstitial scarring.

Goligorsky MS. Postobstructive regeneration of kidney is derailed when surge in renal stem cells during course of unilateral ureteral obstruction is halted. Am J Physiol Renal Physiol 298: F357-F364, 2010. First published November 11, 2009 doi:10.1152/ajprenal.00542.2009.-Unilateral ureteral obstruction (UUO), a model of tubulointerstitial scarring (TIS), has a propensity toward regeneration of renal parenchyma after release of obstruction (RUUO). No information exists on the contribution of stem cells to this process. We performed UUO in FVB/N mice, reversed it after 10 days, and examined kidneys 3 wk after RUUO. UUO resulted in attenuation of renal parenchyma. FACS analysis of endothelial progenitor (EPC), mesenchymal stem (MSC) and hematopoietic stem (HSC) cells obtained from UUO kidneys by collagenase-dispersed single-cell suspension showed significant increase in EPC, MSC, and HSC compared with control. After RUUO cortical parenchyma was nearly restored, and TIS score improved by 3 wk. This reversal process was associated with return of stem cells toward baseline level. When animals were chronically treated with nitric oxide synthase (NOS) inhibitor at a dose that did not induce hypertension but resulted in endothelial dysfunction, TIS scores were not different from control UUO, but EPC number in the kidney decreased significantly; however, parenchymal regeneration in these mice was similar to control. Blockade of CXCR4-mediated engraftment resulted in dramatic worsening of UUO and RUUO. Similar results were obtained in caveolin-1-deficient but not -overexpressing mice, reflecting the fact that activation of CXCR4 occurs in caveolae. The present data show increase in EPC, HSC, and MSC population during UUO and a tendency for these cells to decrease to control level during RUUO. These processes are minimally affected by chronic NOS inhibition. Blockade of CXCR4-stromal cell-derived factor-1 (SDF-1) interaction by AMD3100 or caveolin-1 deficiency significantly reduced the UUO-associated surge in stem cells and prevented parenchymal regeneration after RUUO. We conclude that the surge in stem cell accumulation during UUO is a prerequisite for regeneration of renal parenchyma. fibrosis; caveolin; AMD3100; mesenchymal stem cells GLOMERULOSCLEROSIS and tubulointerstitial scarring (TIS)-the main processes governing progression of chronic renal diseasesare well studied and described (3, 7-9, 11, 15). Unilateral ureteral obstruction (UUO) has been consistently utilized as a convenient model of TIS, although this process is much less pronounced in mice than in rats, rabbits, and dogs (5). This model has provided valuable insights into the molecular and cellular mechanisms of TIS progression. Specifically, the role of various subsets of infiltrating leukocytes, hypoxia, angiotensin II, transforming growth factor (TGF)-␤, TNF-␣, plasminogen activator inhibitor-1, and reactive oxygen species, to name a few, has been established (reviewed in Refs. 3,5,[7][8][9]11,15). Notwithstanding these advances, significant controvers...

We present the case of a 49-year-old male diagnosed with trisomy 21 at an early age, who developed severe intellectual deficiency and progressive muscle weakness of the upper limbs at the age of 47.He also complained of pain in the shoulders, and became unable to move his right arm within months. The symptoms worsened over the following year. He progressively stopped walking, developed dysphagia, further impairment of the lower limbs and eventually died.At the autopsy, the patient presented characteristic craniofacial morphological features of Down syndrome. Macroscopic examination of the brain showed atrophy of the superior temporal gyrus and the frontoparietal cortex, a small hippocampus and dilatation of the lateral ventricles.Microscopic examination of the brain showed typical features of Alzheimer's disease with amyloid deposits in the cerebral cortex, basal ganglia and cerebellar cortex. Gallyas staining showed the presence of numerous neuritic plaques and widespread neurofibrillary degeneration at the level of the hippocampus. Immunohistological stains for alpha synuclein did not reveal the presence of Lewy bodies.The spinal cord examination showed atrophy of the corticospinal tract. CD68 immunohistochemistry revealed abundant macrophages in the medullary pyramids and lateral columns and an associated microglial reaction. TDP-43 immunohistochemistry showed a filamentous staining in the cytoplasm and a loss of nuclear staining within motor-neurons. Ubiquitin immunohistochemistry showed weak staining of some spinal nerve roots.