Activation of Liver X Receptor Inhibits Osteopontin and Ameliorates Diabetic Nephropathy

Abstract

Osteopontin is a proinflammatory cytokine and monocyte chemoattractant implicated in the pathogenesis of diabetic nephropathy. Synthetic agonists for liver X receptors (LXRs) suppress the expression of proinflammatory genes, including osteopontin, but whether LXR activation modulates diabetic nephropathy is unknown. We administered the LXR agonist T0901317 to mice with streptozotocin-induced diabetes and evaluated its effects on diabetic nephropathy. The LXR agonist decreased urinary albumin excretion without altering blood glucose levels and substantially attenuated macrophage infiltration, mesangial matrix accumulation, and interstitial fibrosis. LXR activation suppressed the gene expression of inflammatory mediators, including osteopontin, in the kidney cortex. In vitro, LXR activation suppressed osteopontin expression in proximal tubular epithelial cells by inhibiting AP-1-dependent transcriptional activation of the osteopontin promoter. Taken together, these results suggest that inhibition of renal osteopontin by LXR agonists may have therapeutic potential for diabetic nephropathy.

Urinary Osteopontin Predicts Incident Chronic Kidney Disease, while Plasma Osteopontin Predicts Cardiovascular Death in Elderly Men

“…As described above, treatment with statins and antihypertensive agents has previously been shown to influence osteopontin activity [22]. Remarkably, studies done in mice showed that inhibition of renal osteopontin by liver X receptor agonists may have a therapeutic value for diabetic nephropathy [26], and several other preclinical animal studies using loss-of-function approaches have demonstrated osteopontin as a therapeutic target [27]. Whether the measurement of plasma or urinary osteopontin will be useful in guiding the initiation and monitoring of osteopontin-modulating treatments remains to be established.…”

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

“…This new model of renal disease may be relevant to human disease, since the expression of LXRα and LXRβ is significantly decreased in patients with DN compared with controls [27] and renal biopsies from patients with DN show lipid deposition primarily in glomeruli [41][42][43]. Recent studies looking at LXR action in the kidney have shown improved albuminuria with other LXR ligands (T091317, GW3965) and different animal models of DN (STZ C57Bl/6, STZ Ldlr −/− ) [28,29]; however, these studies were unable to address the importance of LXR in baseline renal function. The authors attributed the improvement in renal function to inhibition of the proinflammatory gene osteopontin in renal tubular cells [29] or to enhanced activity of macrophage LXRα [28].…”

“…Recent studies looking at LXR action in the kidney have shown improved albuminuria with other LXR ligands (T091317, GW3965) and different animal models of DN (STZ C57Bl/6, STZ Ldlr −/− ) [28,29]; however, these studies were unable to address the importance of LXR in baseline renal function. The authors attributed the improvement in renal function to inhibition of the proinflammatory gene osteopontin in renal tubular cells [29] or to enhanced activity of macrophage LXRα [28]. In contrast, our data, supported by loss of function and gain of function (using a gene-selective LXR ligand), suggest a more complex mechanism, which includes protection from lipid deposition in the glomerulus and inhibition of renal inflammation.…”

“…Human biopsies and experimental rodent models have revealed a consistent downregulation of LXRs in DN compared with control [26,27], and experiments with firstgeneration LXR ligands have shown anti-inflammatory and anti-albuminuric actions in diabetic mice [28,29]. While these observations are promising for the development of DN therapies targeting LXRs, several fundamental questions remain.…”

Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy

“…The glomerular fi ltration rate (eGFR) was estimated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula ( 29,30 ). Twentyfour hour urine albumin, protein, and creatinine were available to all patients in the last month prior to biopsy.…”