Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice

Abstract

Aims/hypothesis Liver X receptors (LXRs) α and β are nuclear hormone receptors that are widely expressed in the kidney. They promote cholesterol efflux from cells and inhibit inflammatory responses by regulating gene transcription. Here, we hypothesised (1) that LXR deficiency would promote renal decline in a mouse model of diabetes by accelerating intraglomerular cholesterol accumulation and, conversely, (2) that LXR agonism would attenuate renal decline in diabetes.Methods Diabetes was induced with streptozotocin (STZ) and maintained for 14 weeks in Lxrα/β +/+ (Lxrα, also known as Nr1h3; Lxrβ, also known as Nr1h2) and Lxrα/β −/− mice. In addition, STZ-injected DBA/2J mice were treated with vehicle or the LXR agonist N ,N -dimethyl-hydroxycholenamide (DMHCA) (80 mg/kg daily) for 10 weeks. To determine the role of cholesterol in diabetic nephropathy (DN), mice were placed on a Western diet after hyperglycaemia developed. Results Even in the absence of diabetes, Lxrα/β −/− mice exhibited a tenfold increase in the albumin:creatinine ratio and a 40-fold increase in glomerular lipid accumulation compared with Lxrα/β +/+ mice. When challenged with diabetes, Lxrα/β −/− mice showed accelerated mesangial matrix expansion and glomerular lipid accumulation, with upregulation of inflammatory and oxidative stress markers. In the DN-sensitive STZ DBA/2J mouse model, DMHCA treatment significantly decreased albumin and nephrin excretion (by 50% each), glomerular lipids and plasma triacylglycerol (by 70%) and cholesterol (by 48%); it also decreased kidney inflammatory and oxidative stress markers compared with vehicle-treated mice. Conclusions/interpretation These data support the idea that LXR plays an important role in the normal and diabetic kidney, while showing that LXR, through its inhibitory effect on inflammation and cholesterol accumulation in glomeruli, could also be a novel therapeutic target for DN.

Cordyceps militaris fruit body extract ameliorates membranous glomerulonephritis by attenuating oxidative stress and renal inflammation via the NF-κB pathway

“…27,28 Therefore, the anti-oxidation and antiinflammatory methods and drugs are intensely studied. [29][30][31] The problem is that targeting single or several molecules in the complex signaling pathways generate many adverse side effects. For example, the bardoxolone methyl, a promising antioxidation medicine, generates adverse side effects such as weight loss, muscle spasm, proteinuria, and abnormal high level of serum megnesium and alanine aminotransferase (ALT), and death.…”

CD36 in chronic kidney disease: novel insights and therapeutic opportunities

“…33 However, LXR activation in diabetic kidney models was determined to be renoprotective through mechanisms independent of CD36 but expression levels were not examined in all studies. [48][49][50] Lipids including fatty acids 12 , and Ox-LDL 51 can upregulate CD36 expression. Following CD36-mediated uptake in macrophages, Ox-LDL is metabolized to produce 9-hydroxy octade-cadienoic acid and 13-octade-cadienoic acid.…”

Emerging role of liver X receptors in cardiac pathophysiology and heart failure

“…A homeostatic role for LXRs in kidney function has been postulated. Lxrβ − / − mice exhibit polyuria and polydipsia, features of diabetes insipidus [ 42 ], and mice deficient for both LXRs display a renal phenotype analogous to diabetic nephropathy with elevations in albumin:creatinine ratio and glomerular lipid accumulation [ 99 ]. When challenged with diabetes, these mice demonstrated accelerated mesangial matrix expansion, increased glomerular lipid, and upregulation of inflammatory and oxidative stress markers [ 99 ].…”