title: High Fat High Cholesterol Diet (Western Diet) Aggravates Atherosclerosis, Hyperglycemia and Renal Failure in Nephrectomized LDL Receptor Knockout Mice: Role of Intestine Derived Lipopolysaccharide.
abstract: A high fat meal, frequently known as western diet (WD), exacerbates atherosclerosis and diabetes. Both these diseases are frequently associated with renal failure. Recent studies have shown that lipopolysaccharide (LPS) leaks into the circulation from the intestine in the setting of renal failure and after WD. However, it is not clear how renal function and associated disorders are affected by LPS. This study demonstrates that circulatory LPS exacerbates renal insufficiency, atherosclerosis and glucose intolerance. Renal insufficiency was induced by 2/3 nephrectomy in LDL receptor knockout mice. Nx animals were given normal diet (Nx) or WD (Nx+WD). The controls were sham operated animals on normal diet (control) and WD (WD). To verify if LPS plays a role in exaggerating renal insufficiency, polymyxin (PM), a known LPS antagonist, and curcumin (CU), a compound known to ameliorate chronic kidney disease (CKD), was given to Nx animals on western diet (Nx+WD+PM and Nx+WD+CU, respectively). Compared to control, all other groups displayed increased circulatory LPS. The Nx+WD cohort had the highest levels of LPS. Nx group had significant renal insufficiency and glucose intolerance but not atherosclerosis. WD had intense atherosclerosis and glucose intolerance but it did not show signs of renal insufficiency. Compared to other groups, Nx+WD had significantly higher cytokine expression, macrophage infiltration in the kidney, renal insufficiency, glucose intolerance and atherosclerosis. PM treatment blunted the expression of cytokines, deterioration of renal function and associated disorders, albeit not to the levels of Nx, and was significantly inferior to CU. PM is a non-absorbable antibiotic with LPS binding properties, hence its beneficial effect can only be due to its effect within the GI tract. We conclude that LPS may not cause renal insufficiency but can exaggerate kidney failure and associated disorders following renal insufficiency.
authors.affiliation: Divisions of Nephrology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Siddhartha S
authors.initials: SS
authors.lastname: Ghosh
authors.affiliation: Divisions of Nephrology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Samuel
authors.initials: S
authors.lastname: Righi
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Krieg
authors.affiliation: Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Le
authors.initials: L
authors.lastname: Kang
authors.affiliation: Divisions of Nephrology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Carl
authors.affiliation: Division of Pulmonary Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: H Davis
authors.initials: HD
authors.lastname: Massey
authors.affiliation: Divisions of Nephrology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Domenic A
authors.initials: DA
authors.lastname: Sica
authors.affiliation: Divisions of Nephrology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Todd W B
authors.initials: TW
authors.lastname: Gehr
authors.affiliation: Division of Pulmonary Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Shobha
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000009:adverse effects; D003474:Curcumin / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects*; D066273:Diet, Western / Q000009:adverse effects*; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D015870:Gene Expression; D018149:Glucose Intolerance / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006943:Hyperglycemia / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009392:Nephrectomy / Q000009:adverse effects; D011113:Polymyxins / Q000494:pharmacology; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D051437:Renal Insufficiency / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control
chemical_list: D004041:Dietary Fats; D008070:Lipopolysaccharides; D011113:Polymyxins; D011973:Receptors, LDL; D002784:Cholesterol; D003474:Curcumin