Role of Sterol Regulatory Element-binding Protein 1 in Regulation of Renal Lipid Metabolism and Glomerulosclerosis in Diabetes Mellitus

Sun, Lijun; Halaihel, Nabil; Zhang, Weiping; Rogers, Thomas E.; Levi, Moshe

doi:10.1074/jbc.m110650200

Cited by 298 publications

(278 citation statements)

References 41 publications

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“…29,30 Overexpressing the active form of SREBP-1 in the kidneys of mice induces proteinuria. 31 Our results suggest, for the first time, that activation of SREPBs and accumulation of lipids within the kidney also occur in LN.…”

Section: Discussionmentioning

confidence: 76%

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Nowling

Mather²,

Thiyagarajan

et al. 2015

Journal of the American Society of Nephrology

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Nearly one half of patients with lupus develop glomerulonephritis (GN), which often leads to renal failure. Although nephritis is diagnosed by the presence of proteinuria, the pathology of nephritis can fall into one of five classes defined by different forms of tissue injury, and the mechanisms involved in pathogenesis are not completely understood. Glycosphingolipids are abundant in the kidney, have roles in many cellular functions, and were shown to be involved in other renal diseases. Here, we show dysfunctional glycosphingolipid metabolism in patients with lupus nephritis and MRL/lpr lupus mice. Specifically, we found that glucosylceramide (GlcCer) and lactosylceramide (LacCer) levels are significantly higher in the kidneys of nephritic MRL/lpr lupus mice than the kidneys of non-nephritic lupus mice or healthy controls. This elevation may be, in part, caused by altered transcriptional regulation and/or activity of LacCer synthase (GalT5) and neuraminidase 1, enzymes that mediate glycosphingolipid metabolism. We show increased neuraminidase 1 activity early during the progression of nephritis (before significant elevation of GlcCer and LacCer in the kidney). Elevated levels of urinary LacCer were detected before proteinuria in lupus mice. Notably, LacCer levels were higher in the urine and kidneys of patients with lupus and nephritis than patients with lupus without nephritis or healthy controls. Together, these results show early and significant dysfunction of the glycosphingolipid metabolic pathway in the kidneys of lupus mice and patients with lupus nephritis and suggest that molecules in this pathway may serve as early markers in lupus nephritis.

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Section: Discussionmentioning

confidence: 76%

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Nowling

Mather²,

Thiyagarajan

et al. 2015

Journal of the American Society of Nephrology

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“…These changes were consistent with the effects of aging and CR on the expression of nuclear SREBP-1 and SREBP-2. In the SREBP-1a transgenic mouse, we have found increased renal expression of TGF-␤ and VEGF as well as increased expression of type IV collagen and fibronectin, well-established mediators of glomerulosclerosis and proteinuria (19). In addition, cell culture studies have shown that in mesangial cells, LDL or VLDL induces upregulation of TGF-␤ and PAI-1 and accumulation of ECM proteins (40 -42).…”

Section: Role Of Altered Lipid Metabolism In Renal Diseasementioning

confidence: 93%

“…We reported previously that in SREBP-1a transgenic mice overexpressing SREBP-1 in kidney, in the absence of any increases in serum glucose, triglyceride, or cholesterol, there were increased renal triglyceride accumulation and upregulation of TGF-␤ and VEGF, resulting in accumulation of fibronectin and type IV collagen, glomerulosclerosis, and proteinuria (19). Therefore, our main purpose in this study was to determine whether the effects of CR are mediated at least in part by the modulation of renal lipid metabolism.…”

Section: Cr Prevents Age-related Increase In Lipid Accumulation and Imentioning

confidence: 99%

“…In SREBP-1a transgenic mice, in the absence of any changes in serum glucose or serum lipids, there is increased accumulation of triglyceride and cholesterol in the kidney, associated with increased expression of TGF-␤, vascular endothelial growth factor (VEGF), and the extracellular matrix (ECM) proteins type IV collagen and fibronectin, resulting in glomerular hypertrophy, glomerulosclerosis, and proteinuria (19). These renal alterations are very similar to the renal pathology in diabetic and aging animals (1-3).…”

mentioning

confidence: 99%

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Calorie Restriction Modulates Renal Expression of Sterol Regulatory Element Binding Proteins, Lipid Accumulation, and Age-Related Renal Disease

Jiang¹,

Liebman²,

Lucia³

et al. 2005

Journal of the American Society of Nephrology

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Sterol regulatory element binding proteins (SREBP) are major regulators of fatty acid and cholesterol synthesis. This study found that age-related renal matrix deposition and proteinuria were associated with increased renal expression of SREBP-1 and SREBP-2 and increased renal accumulation of triglyceride and cholesterol. Because calorie restriction (CR) modulates age-related renal disease, it then was determined whether the effects of CR are mediated partially by modulation of renal lipid metabolism. Compared with ad libitum (AL)-fed 24-month-old (24m) F344BN rats, CR resulted in significant decreases in extracellular matrix accumulation (periodic acid-Schiff staining and immunofluorescence of type IV collagen and fibronectin) and proteinuria. A significant decrease was also observed in the renal expression of growth factors (connective tissue growth factor and vascular endothelial growth factor) and matrix metalloproteinase inhibitor (plasminogen activator inhibitor-1). These structural and functional changes were associated with significant decreases in renal nuclear SREBP-1 (5.2 in 24m AL versus 3.3 densitometry units in 24m CR; P < 0.01) and SREBP-2 (7.1 in 24m AL versus 4.1 densitometry units in 24m CR; P < 0.01) protein abundance and renal triglyceride and cholesterol contents. It is interesting that serum leptin level was significantly increased as a function of aging, and CR resulted in significant reduction in serum leptin level. Because it was shown previously that increased renal expression of SREBP-1a per se caused renal lipid accumulation, glomerulosclerosis, and proteinuria, the results suggest that CR modulates age-related renal disease in part by modulation of renal SREBP expression and renal lipid accumulation.

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“…In fact, it was recently reported that the CRE at −177 in the mouse HKα2 promoter played a functional role in regulating gene expression [23]. Similarly, NF-κB inhibits transcription of HKα2 in a mouse medullary collecting duct cell line [24]; a putative NF-κB site is located at −486 in the rabbit HKα2 promoter.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the rabbit HKα2 gene promoter

Zies¹,

Gumz²,

Wingo³

et al. 2006

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

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The HKα2 gene directs synthesis of the HKα2 subunit of the H + , K + -ATPase. In the kidney and colon, the gene is highly expressed and is thought to play a role in potassium (K + ) conservation. The rabbit has been an important experimental system for physiological studies of ion transport in the kidney, so the rabbit HKα2 gene has been cloned and characterized. The genomic clones and the previously reported HKα2a and HKα2c subunit cDNAs provided a means to address several issues regarding the structure and expression of HKα2 gene. First, the genomic organization established that the rabbit HKα2 gene was unambiguously homologous to the mouse HKα2 gene and the human ATP1AL1 gene. Second, the mapping of the transcription start site for the alternate transcript, HKα2c, confirmed that it was an authentic rabbit transcript. Finally, isolation of DNA from the 5' end of the HKα2 gene enabled us to initiate studies on its regulation in the rabbit cortical collecting duct. The promoter and two putative negative regulatory regions were identified and the effect of cell confluency on gene expression was studied.

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Role of Sterol Regulatory Element-binding Protein 1 in Regulation of Renal Lipid Metabolism and Glomerulosclerosis in Diabetes Mellitus

Cited by 298 publications

References 41 publications

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

Calorie Restriction Modulates Renal Expression of Sterol Regulatory Element Binding Proteins, Lipid Accumulation, and Age-Related Renal Disease

Characterization of the rabbit HKα2 gene promoter

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