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.
Highlights
Kidney failure is frequently associated with hypertension, glucose intolerance and cardiovascular disorders such as atherosclerosis
Population based studies have determined that excess body weight was a strong independent risk factor for end stage renal disease (ESRD) even after adjustment for other major risk factors that are associated with ESRD [2]
The mechanisms by which obesity/metabolic syndrome due to high fat diet exacerbate renal failure remain elusive and largely speculative. To understand this mechanism we investigated the effect of high fat high cholesterol diet, known as western diet, on LDL receptor knockout (LDLR-/-) mice with renal failure
Summary
Kidney failure is frequently associated with hypertension, glucose intolerance and cardiovascular disorders such as atherosclerosis. The mechanisms by which obesity/metabolic syndrome due to high fat diet exacerbate renal failure remain elusive and largely speculative. Others have shown that partial nephrectomized LDLR-/- mice on western diet have vascular calcification, osteodystrophy and hyperphosphatemia [5] Apoe knockout mice, another mouse model of atherosclerosis, have accelerated atherogenesis following uremia [6,7]. ApoE knockout mice have high cholesterol (400 to 500 mg/dL) and atherosclerotic lesions whereas, the chow-fed LDLR-/- mice have mildly increased plasma cholesterol levels (175 to 225 mg/dL) and usually do not develop significant atherosclerotic lesions [8] Since environmental factors such as diet govern the development of atherosclerosis and glucose intolerance in LDLR-/- mice, we theorized that the nephrectomized LDLR-/- mouse will be a suitable model to elucidate the mechanism by which western diet can influence hypertension, renal dysfunction, glucose intolerance and atherosclerosis
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