Search

Background. Under proteinuric conditions, ultrafiltrated albumin can induce an inflammatory and fibrotic response in proximal tubular cells. It is unclear whether albumin per se or compounds bound to albumin are nephrotoxic. Some studies have supported the toxicity of albumin-bound fatty acids; however, these compared untreated, fatty acid containing, albumin and delipidated albumin. To prevent confounding by the delipidation procedure, we compared delipidated albumin and oleic acid (OA)-loaded delipidated albumin in two models: the classical rat protein overload and the Axolotl. The latter had an amphibian kidney with a subset of nephrons that drained the peritoneal cavity, so that i.p. injection of albumin selectively targeted open but not closed nephrons and was used to prevent removal of fatty acids from albumin in the circulation. Methods. Protein overload was induced in Wistar rats (groups n = 8, for 12 weeks) and Axolotl (groups n = 10, for 10 days) by daily i.p. injections of 1 g (rat) or 50 mg (Axolotl) of fatty acid-free bovine serum albumin (BSA), fatty acid-free BSA with addition of six molecules of oleic acid (OA-BSA) or saline (SAL). Results. After 12 weeks, proteinuria and SBP were increased in BSA and OA-BSA rats compared to saline-injected controls (P < 0.05), but OA loading had no additional effect compared to albumin alone. This was also true for glomerular and interstitial inflammation, fibrotic changes and focal glomerulosclerosis (OA-BSA versus BSA, all P = ns). Axolotls injected with OA-loaded albumin showed comparable protein storage in tubular epithelial cells, tubular dilatation and peritubular fibrosis around tubules draining the peritoneal cavity compared with Axolotls injected with albumin alone. This was also true for TGF-β (inflammation marker) and collagen I (fibrosis marker) (OA-BSA versus BSA, all P = ns). Conclusions. In the Axolotl and chronic rat model, OA loading of albumin did not aggravate renal damage compared to albumin alone. Although in vitro studies clearly show induction of changes in cultured tubular epithelial cells exposed to albumin-bound fatty acids that are consistent with a role in induction of tubulointerstitial disease, our experiments suggest that currently available models for demonstrating such an effect in vivo are insufficient. [ABSTRACT FROM AUTHOR]

Background. Remodelling of the heart, characterized by hypertrophy, fibrosis and capillary/myocyte mismatch, is observed in patients with chronic renal failure. Low vitamin D levels have been associated with increased cardiovascular risk. In the present experimental study, we studied the effects of non-hypercalcaemic doses of calcitriol on microvascular disease and interstitial fibrosis of the heart. Methods. Three-month-old male Sprague-Dawley rats were randomized to subtotal nephrectomy (SNX) or sham operation and received calcitriol (6 ng/kg) or vehicle starting immediately thereafter. Blood pressure was measured by tail pletysmography. Albuminuria was measured by rat-specific ELISA. Capillary length density, volume density of interstitial tissue, immunohistochemistry and western blots (vitamin D receptor, collagen I, III, TGF-β1, MAP kinases and nitrotyrosine) were assessed after 12 weeks of treatment. Results. After SNX blood pressure, albuminuria and heart weight were elevated, capillary length density reduced and interstitial fibrosis increased. Treatment with calcitriol reduced albuminuria and prevented reduction of capillary density and expansion of interstitium without affecting significant blood pressure and heart weight after perfusion fixation. Calcitriol left high VEGF unchanged, but upregulated VEGF receptor 2 (presumably reversing VEGF resistance). Calcitriol reduced expression of profibrotic TGF-β1 and the accumulation of collagens I and III. Conclusions. Non-hypercalcaemic doses of calcitriol ameliorated, directly or indirectly, cardiac remodelling in sub- totally nephrectomized rats. [ABSTRACT FROM AUTHOR]