Role of oxidized low density lipoproteins and free fatty acids in the pathogenesis of glomerulopathy and tubulointerstitial lesions in type 2 diabetes

doi:10.1016/j.numecd.2010.10.002

Nutrition, Metabolism and Cardiovascular Diseases

Volume 21, Issue 2, February 2011, Pages 79-85

https://doi.org/10.1016/j.numecd.2010.10.002 Get rights and content

Abstract

Oxidized lipids initiate and modulate the inflammatory cellular events in the arterial wall and the formation of macrophage foam cells. CD36 mediates the cellular uptake of ox-LDL through its recognition of specific truncated fatty acid moieties and oxidized phosphatidylcholine. Evidence has been reported that chemokine CXCL16, rather than CD36, is the main scavenger receptor in human podocytes mediating the uptake of ox-LDL. Ox-LDL induces loss of nephrin expression from cultured podocytes. It has been recently shown that nephrin once phosphorilated associates with PI3K and stimulates the Akt dependent signaling. This pathway plays a critical role in nephrin-actin-dependent cytoskeleton activation and remodeling, in the control of protein trafficking and in podocyte survival. An enhanced FFA uptake by podocytes is mediated by increased C36 scavenger receptor expression, together with a decrease of betaoxidation and in turn intracellular lipid accumulation. Accumulated FFA that is trapped into the mitochondrial matrix leads to mitochondrial ROS production, lipid peroxidation and mitochondrial damage and dysfunction. A disturbed transport and oxidation of FFA, paralleled by an impaired antioxidant response, damages podocyte structure and leads to glomerulopathy in early stages of nephrosis. Increased triglyceride synthesis and ox-and glycated LDL uptake by mesangial cells may also contribute to determine diabetic glomerulopathy. Oxidative processes are pivotal events in injury to renal tubular and epithelial cells exposed to ox-LDL. Notably CXCL16 are the main receptors for the uptake of ox-LDL in podocytes, whereas CD36 plays this role in tubular renal cells. In overt type 2 diabetes Ox-LDL and FFA damage podocyte function, SD-podocyte structure and tubulointerstitial tissue, at least partially, through different pathogenetic mechanisms.

Further studies are needed to investigate the role of Ox-LDL and FFA on renal complications in obese, insulin resistant patients before the development of diabetes. The aim of the present review is to briefly elucidate the patterns of systemic lipid metabolism and the individual effects of lipotoxicity at glomerular and tubular level in the kidney of overt type 2 diabetic patients. These findings better elucidate our knowledge of diabetic glomerulopathy, beside and along with previous findings, in vivo and in vitro, on ox-LDL and FFA effects in mesangial cells.

Section snippets

Lipid metabolism in obese insulin resistant and type 2 diabetic patients

Unlike Type 1 diabetes that has insulin deficiency due to massive destruction of pancreatic beta cells, Type 2 diabetes has relative insulin deficiency secondary to insulin resistance often associated with obesity. In early stages of obesity insulin action is still preserved or even enhanced as far as its action on lipogenesis and adipogenesis, particularly in liver and skeletal muscle. Ectopic fat accumulation damages muscle and liver metabolic response to insulin and may lead to impaired

Lipotoxicity and podocytes

Podocytes modulate glomerular size-selectivity barrier to proteins [20], [21], [22]. Different slit diaphragm (SD)-associated proteins, such as nephrin, CD2-associated protein, podocin and alpha actin 4, contribute to maintain glomerular size selective permeability [23], [24], [25], [26], [27]. The critical role of nephrin has emerged in type 2 diabetic patients with microalbuminuria [6], [7], as well as in other patients with nephrotic syndrome [23], [24], [25], [26], [27].

Gutwein et al. [25],

Lipotoxicity and tubulointerstitial tissue

Oxidative processes are pivotal events in the injury to renal tubular epithelial cells exposed to ox-LDL. CXCL16 is one of the few scavenger receptors, known to bind ox-LDL, that is found in two distinct forms: membrane bound and soluble. Surface expressed CXCL16 binds and internalizes ox-LDL. CXCL16 are the main receptors for the uptake of ox-LDL in podocytes, whereas CD36 plays this role in tubular renal cells [24], [25], [26], as well as in macrophages as previously described [6], [8]. Heme

Conclusions

Obesity is often associated with type 2 diabetes and obese patients are prone to develop renal lesions, such as focal segmental sclerosis. Adipogenesis is activated in fat, skeletal muscle and liver tissues in obesity, whereas lipolysis in adipose tissue prevails in type 2 diabetes. Unfortunately scanty information is available on the course of renal function in insulin resistant obese patients, before the development of overt diabetes. Interestingly nephrotic syndrome, is also associated with

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ReviewRole of oxidized low density lipoproteins and free fatty acids in the pathogenesis of glomerulopathy and tubulointerstitial lesions in type 2 diabetes

Abstract

Section snippets

Lipid metabolism in obese insulin resistant and type 2 diabetic patients

Lipotoxicity and podocytes

Lipotoxicity and tubulointerstitial tissue

Conclusions

Nutr Metab Cardiovasc Dis

Nutr Metab Cardiovasc Dis

Nutr Metab Cardiovasc Dis

Metabolism

J Am J Pathol

Kidney Int

Kidney Int

Am J Pathol

J Biol Chem

Metabolism

Patterns of renal injury in NIDDM patients with microalbuminuria

Diabetologia

Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate

Diabetes

Structural-functional relationships in diabetic nephropathy

J Clin Invest

Glomerular structure and function in diabetic nephropathy. Early to advanced stages

Diabetes

Cellular lipid metabolism and the role of lipids in progressive renal disease

Am J Nephrol

The role of lipids in renal disease. Future challenges

Kidney Int

Effects of different LDL particles on inflammatory molecules in human mesangial cells

Diabetolgia

Altered transcapillary escape of albumin and microalbuminuria reflect two different pathogenetic mechanisms

Diabetes

Increased renal arterial resistance predicts the course of renal function in type 2 diabetes with microalbuminuria

Diabetes

Risk factors for renal dysfunction in type 2 diabetes: UK 74

Diabetes

Is nonalbuminuric renal insufficiency in type 2 diabetes related to an increase in intrarenal vascular disease?

Diabetes Care

Review
Role of oxidized low density lipoproteins and free fatty acids in the pathogenesis of glomerulopathy and tubulointerstitial lesions in type 2 diabetes