Oleic acid loading does not add to the nephrotoxic effect of albumin in an amphibian and chronic rat model of kidney injury.
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-beta (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.
van Timmeren
Mirjan M
MM
University Medical Center Groningen, University of Groningen, Department of Pathology and Laboratory Medicine, Groningen, The Netherlands. m.m.van.Timmeren@med.umcg.nl
Gross
Marie-Luise
ML
Hanke
Wilfried
W
Klok
Pieter A
PA
van Goor
Harry
H
Stegeman
Coen A
CA
Bakker
Stephan J L
SJ
D000557:Ambystoma; D000818:Animals; D002417:Cattle; D004195:Disease Models, Animal; D004347:Drug Interactions; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D019301:Oleic Acid / Q000008:administration & dosage / Q000633:toxicity*; D011507:Proteinuria / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D013045:Species Specificity
D005227:Fatty Acids; D012710:Serum Albumin, Bovine; D019301:Oleic Acid