Lipid Accumulation and Transforming Growth Factor-β Upregulation in the Kidneys of Rats Administered Angiotensin II

Abstract

Abstract-Abnormal lipid metabolism may play a role in progressive renal failure. We studied whether lipid accumulation occurs and whether lipid deposits are colocalized with transforming growth factor-␤1 (TGF-␤1) in the kidney of angiotensin II-infused animals. Oil red O staining showed marked lipid deposition in the tubular epithelial and vascular wall cells of angiotensin II-treated but not in norepinephrine-treated rats. Histological analyses showed that increased amounts of superoxide and intense TGF-␤1 mRNA expression were present in lipid-positive tubular epithelial cells in angiotensin II-infused animals. Protein expression of sterol regulatory element-binding protein 1 (SREBP-1) and mRNA expression of fatty acid synthase in the kidney were Ϸ3 times and 1.5 times, respectively, higher in angiotensin II-treated rats than in controls. Treatment of angiotensin II-infused animals with an iron chelator, deferoxamine, attenuated the angiotensin II-induced increases in renal expression of SREBP-1 and fatty acid synthase and normalized the lipid content in the renal cortical tissues. Abnormal lipid metabolism may be associated with upregulation of TGF-␤1 expression and aberrant iron homeostasis in the kidneys of angiotensin II-infused animals. Key Words: angiotensin II Ⅲ transforming growth factors Ⅲ lipids P revious studies showed that accumulation of lipids in nonadipose tissues occurs in certain diseased conditions, and that it plays a crucial role in the pathogenesis of tissue damage, 1 a phenomenon referred to as lipotoxicity. 2 For example, lipid deposition in the arterial wall 3,4 is postulated to represent an early event in the development of atherosclerosis. 5 The accumulation of triglycerides (TGs) in cardiomyocytes 6,7 may be associated with contractile dysfunction, and excess TGs in the liver may promote hepatic fibrosis. 8 Lipid accumulation in the kidney may represent features of glomerular and tubulointerstitial damage. 9 We found that long-term administration of angiotensin II (Ang II) to rats caused marked deposition of iron 10 and upregulation of the expression of transforming growth factor-␤1 (TGF-␤1) in renal tubular epithelial cells. 11 We also found that iron chelation attenuated the Ang II-induced upregulation of TGF-␤1 in the kidney, suggesting a possible link between aberrant iron homeostasis and TGF-␤1 upregulation. However, unexpectedly, histological analysis showed that upregulation of TGF-␤1 mRNA and deposition of iron occurred in different tubular cells in most cases. The aims of the present study were to investigate whether accumulation of lipids occurs in the kidney of Ang II-infused animals and to investigate the relationship between lipid accumulation and TGF-␤1 in terms of localization. We also investigated whether Ang II infusion alter the expression of genes that have relation to the lipid metabolism, such as ATP-binding cassette transporter subfamily A-1 (ABCA1), scavenger receptor class B type 1 (SR-B1), sterol regulatory elementbinding protein 1 (SREBP-1), SREBP-2, 3-hydrox...

Angiotensin II-Induced Regulation of the Expression and Localization of Iron Metabolism-Related Genes in the Rat Kidney

“…1, 2); these results stood in contrast with the exclusive co-localization of ferritin and heme oxygenase-1 (15). In addition, only a fraction of the mRNA expression of the genes tested was colocalized with lipid deposition, again in contrast to the exclusive co-localization of TGF-β1 mRNA and lipid deposition in the kidney (16,17).…”

“…The sequence targeted for the amplification of DMT1 was a common region of DMT1 with or without iron-responsive element (IRE), which was designated here as IRE(+)DMT1 and IRE(−)DMT1, respectively. Rat cDNA corresponding to these iron metabolism-related genes were subcloned into a pGEM-T vector, and then in situ hybridization was performed as described previously (17). After digestion with a restriction enzyme and linearization of the plasmid, antisense and sense cRNA riboprobes were transcribed in vitro using the DIG RNA labeling Kit SP6/T7 (Roche Diagnostics, Basel, Switzerland).…”

“…We previously found that angiotensin II infusion causes a marked accumulation of lipids in the tubular epithelial cells, and this lipid deposition co-localized with the expression of transforming growth factor-β1 (TGF-β1) mRNA (17). We therefore characterized the localization of lipid deposition in relation to the expression of iron metabolism-related genes (Fig.…”

The conflicting effects of maternal nutrient restriction and early-life obesity on renal health

“…In the first instance, increased exposure to angiotensin II induces a rise in cell proliferation, particularly of mesangial cells (62) . As observed with other hormones, plasma concentrations of angiotensin II increase with obesity and, as noted for IGF-I and insulin, angiotensin II is also associated with lipid and collagen accumulation in renal tissue (63)(64)(65) . Long-term exposure to angiotensin II, due to its contractile actions as well as the subsequent increase in metabolic activity in proximal tubules, leads to an increase in oxygen consumption producing renal ischaemia (66) .…”

Pioglitazone Reduces Vascular Lipid Accumulation in Angiotensin II-Induced Hypertensive Rat

“…Activation of the renin-angiotensin system plays a key role in the progression of various diabetic complications and also leads to vascular dysfunction 7,8) . In a recent study, we showed that administration of angiotensin II caused marked lipid accumulation in the heart and kidney in a rat model of hypertension 9,10) . Furthermore, it has been reported that lipids are ligands for transcriptional regulators of the peroxisome proliferator-activated receptor (PPAR) family; therefore, regulating lipid delivery may have a significant impact on PPAR function 5) .…”