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Background. Non-esterified fatty acids (NEFA) carried on albumin may have a causal role in the development of chronic proteinuria-induced nephropathy. To investigate whether NEFA aggravate renal structural damage, we studied the effects of NEFA addition to delipidated bovine serum albumin (BSA) in protein-overload nephropathy.Methods. Three groups of Wistar rats received daily intraperitoneal injections (3 weeks) of either 1 g NEFA-free BSA (BSA-0), or NEFA-free BSA with three (BSA-3) or six (BSA-6) molecules oleic acid added per BSA molecule. An additional group received saline injections only (SAL). Renal damage was evaluated by immunohistochemistry and RT–PCR.Results. Interstitial and glomerular alpha-smooth muscle actin (α-SMA, marker of myofibroblast transformation) expression were higher in BSA-3/6 than in saline-injected controls (P<0.001). Glomerular macrophage influx and desmin (marker of glomerular epithelial cell damage) expression were higher in all BSA-injected rats than SAL (P<0.001). Interstitial macrophage influx was elevated in BSA-0/3 (P<0.05) and BSA-6 (P<0.001) compared to SAL. Addition of six molecules of oleic acid to BSA revealed higher interstitial and glomerular α-SMA expression (P<0.001), increased interstitial macrophage numbers (P<0.001) and enhanced glomerular desmin expression (P<0.05) compared to BSA-0. RT–PCR revealed higher glomerular α-SMA mRNA expression in BSA-3/6 than SAL (P<0.001 and 0.05, respectively), interstitial α-SMA mRNA was elevated in BSA-6 (P<0.05). Interstitial TGF-β1 mRNA expression was significantly higher in BSA-3 than SAL (P<0.05).Conclusions. These data show that addition of oleic acid to NEFA-free BSA aggravates renal damage, suggesting a role for NEFA in the pathogenesis of proteinuric nephropathies. [ABSTRACT FROM AUTHOR]

Background. Advanced glycation end-products (AGEs) contribute to the pathogenesis of diabetic glomerulopathy. The role of AGEs in non-diabetic renal damage is not well characterized. First, we studied whether renal AGE accumulation occurs in non-diabetic proteinuria-induced renal damage and whether this is ameliorated by renoprotective treatment. Secondly, we investigated whether renal AGE accumulation was due to intrarenal effects of local protein trafficking.Methods. Pentosidine was measured (by high-performance liquid chromatography) in rats with chronic bilateral adriamycin nephropathy (AN), untreated and treated with lisinopril. Age-matched healthy rats served as negative controls. Secondly, we compared renal pentosidine in mild proteinuric and non-proteinuric kidneys of unilateral AN and in age-matched controls at 12 and 30 weeks. Intrarenal localization of pentosidine was studied by immunohistochemistry.Results. Renal pentosidine was elevated in untreated AN (0.14±0.04 µmol/mol valine) vs healthy controls (0.04±0.01 µmol/mol valine, P<0.01). In lisinopril-treated AN, pentosidine was lower (0.09±0.02 µmol/mol valine) than in untreated AN (P<0.05). In unilateral proteinuria, pentosidine was similar in non-proteinuric and proteinuric kidneys. After 30 weeks of unilateral proteinuria, pentosidine was increased in both kidneys (0.26±0.10 µmol/mol valine) compared with controls (0.18±0.06 µmol/mol valine, P<0.05). Pentosidine (AN, week 30) was also increased compared with AN at week 12 (0.16±0.06 µmol/mol valine, P<0.01). In control and diseased kidneys, pentosidine was present in the collecting ducts. In proteinuric kidneys, in addition, pentosidine was present in the brush border and cytoplasm of dilated tubular structures, i.e. at sites of proteinuria-induced tubular damage.Conclusion. Pentosidine accumulates in non-diabetic proteinuric kidneys in damaged tubules, and renoprotective treatment by angiotensin-converting enzyme (ACE) inhibitors inhibits AGE accumulation, supporting a relationship between abnormal renal protein trafficking, proteinuria-induced tubular damage and tubular pentosidine accumulation. Future studies, applying specific AGE inhibitors, should be conducted to provide insight into the pathophysiological significance of renal AGEs in non-diabetic renal disease. [ABSTRACT FROM AUTHOR]

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. Advanced glycation end products (AGEs) are involved in diabetic nephropathy (DN). The AGE formation inhibitor pyridoxamine (PM) is renoprotective in DN and in normoglycaemic obese Zucker rats. In chronic allograft nephropathy (CAN), renal AGE accumulation occurs as well. Methods. To investigate whether inhibition of AGE formation is renoprotective in CAN, we studied the Fisher 344 to Lewis (F–L) allograft rat model of experimental CAN. Fisher to Fisher (F–F) isografts served as controls. Proteinuria, renal function and renal histology of untreated transplanted rats (F–L n = 8, F–F n = 8) were compared to rats receiving PM 2 g/l in drinking water for 20 weeks starting at transplantation (F–L n = 5, F–F n = 10). All rats received cyclosporin A (1.5 mg/kg/day) for 10 days after transplantation to prevent early acute rejection. Results. Compared to untreated allografts, PM significantly decreased proteinuria (76 ± 18 vs 29 ± 3 mg/day), serum creatinine (130 ± 12 vs 98 ± 5 μmol/l), focal glomerulosclerosis (116 ± 27 vs 16 ± 5 AU), glomerular macrophage influx (5.6 ± 0.6 vs 3.3 ± 1.0), interstitial fibrosis (132 ± 24 vs 76 ± 2 AU) and interstitial macrophage influx (47.0 ± 8.7 vs 15.4 ± 5.0. Moreover, PM significantly ameliorated tubular accumulation of pentosidine, compared to untreated allografts (2.5 ± 0.6 vs 0.3 ± 0.3, all p Conclusion. PM exerts renoprotective effects and decreases renal pentosidine accumulation in experimental CAN, suggesting a detrimental role for renal AGE accumulation in the pathogenesis of renal damage in this non-diabetic model. These results indicate that inhibition of AGE formation might be a useful adjunct therapy to attenuate CAN. [ABSTRACT FROM AUTHOR]