Connexin 37 is localized in renal epithelia and responds to changes in dietary salt intake.

Connexins are the main components of gap junction channels, which are important for intercellular communication. In the kidney, several members of the connexin (Cx) family have been identified. Renal vascular expression and hemodynamic impacts have so far been shown for Cx37, Cx40, and Cx43. Additionally, Cx30, Cx30.3, and Cx43 have been identified to be part of tubular epithelial gap junctions and/or hemichannels. However, the localization and role of other Cx family members in renal epithelial structures remain undetermined. We aimed to localize Cx37 in the kidney to obtain information on its epithelial expression and potential functions. Immunohistochemistry in rodent kidney showed characteristic punctate patterns in the vasculature and along the nephron. Strong basolateral expression was found in the thick ascending limb and distal convoluted tubule. Weaker abundances were found in the proximal tubule and the collecting duct also at the basolateral side. In situ hybridization and real-time PCR of isolated nephron segments confirmed this distribution at the mRNA level. Ultrastructurally, Cx37 immunostaining was confined to basolateral cell interdigitations and infoldings. As a functional approach, rats were fed low- or high-salt diets. Compared with control and high-salt diets, rats treated with low-salt diet showed significantly increased Cx37 mRNA and protein levels. This may be indicative of an adaptive tubular response to changes in sodium reabsorption. In summary, renal epithelia express Cx37 in their basolateral membranes. Here, the formation of Cx37 gap junctions may be involved in cellular communication and adjustments of vectorial epithelial transport.

Indolent course of tubulointerstitial disease in a mouse model of subpressor, low-dose nitric oxide synthase inhibition.

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.