The role of tubular injury in diabetic nephropathy

Magri, Caroline Jane; Fava, Stephen

doi:10.1016/j.ejim.2008.12.012

Cited by 96 publications

(74 citation statements)

References 69 publications

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“…Chronically activated kidney injury molecule-1 in PT promoted a proinflammatory response and kidney fibrosis in an animal model of CKD (15). Thus, accumulating evidence suggests that injured PTs might be a triggering site of tubulointerstitial fibrosis and the progression of diabetic CKD (23). These findings have been strongly supported by a recent study (40) that showed an association of lower levels of tubular injury with the regression of microalbuminuria in patients with type 1 diabetes.…”

Section: Discussionsupporting

confidence: 76%

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Aquaporin 11 variant associates with kidney disease in type 2 diabetic patients

Choma

Vanacore

Naylor

et al. 2016

American Journal of Physiology-Renal Physiology

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Kidney disease, a common complication of diabetes, associates with poor prognosis. Our previous animal model studies linked aquaporin (AQP)11 to acute kidney injury, hyperglycemia-induced renal impairment, and kidney disease in diabetes. Here, we report the AQP11 rs2276415 variant as a genetic factor placing type 2 diabetic patients at greater risk for the development of kidney disease. We performed two independent retrospective case-control studies in 1,075 diabetic and 1,619 nondiabetic individuals who were identified in the Synthetic Derivative Database with DNA samples in the BioVU DNA repository at Vanderbilt University (Nashville, TN). A χ2-test and multivariable logistic regression analysis with adjustments for age, sex, baseline serum creatinine, and underlying comorbid disease covariates showed a significant association between rs2276415 and the prevalence of any event of acute kidney injury and chronic kidney disease (CKD) in diabetic patients but not in patients without diabetes. This result was replicated in the second independent study. Diabetic CKD patients over 55 yrs old with the minor AQP11 allele had a significantly faster progression of estimated glomerular filtration rate decline than patients with the wild-type genotype. Three-dimensional structural analysis suggested a functional impairment of AQP11 with rs2276415, which could place diabetic patients at a higher risk for kidney disease. These studies identified rs2276415 as a candidate genetic factor predisposing patients with type 2 diabetes to CKD.

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Section: Discussionsupporting

confidence: 76%

“…A significant proportion of AKI cases involve tubular injury, and proximal tubules (PTs) are specifically susceptible to tubular damage and dysfunction (3,35). There is increasing awareness that in addition to the glomerulus, PT may be a target in diabetic kidney disease, and PT injury might be an important contributor to the development of diabetic CKD (23).…”

mentioning

confidence: 99%

Aquaporin 11 variant associates with kidney disease in type 2 diabetic patients

Choma

Vanacore

Naylor

et al. 2016

American Journal of Physiology-Renal Physiology

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“…It also emphasizes the increasingly recognized importance of the tubulointerstitium in diabetic renal disease. [34][35][36][37] Further studies investigating the role of renal fructokinase in both AKI and CKD appears to be warranted.…”

Section: Discussionmentioning

confidence: 99%

Endogenous Fructose Production and Fructokinase Activation Mediate Renal Injury in Diabetic Nephropathy

Lanaspa

Ishimoto

Cicerchi

et al. 2014

Journal of the American Society of Nephrology

141

146

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Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase-deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.

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“…In fact, tubular lesions have been found in diabetics even when the urinary albumin excretion rate is within a normal range. It has been reported that tubular lesions and renal interstitial fibrosis are more closely correlated to renal function than is glomerular sclerosis (Magri & Fava 2009). AGE conjugates with RAGE to activate PKC and increases the production of cytokines (Kanwar et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats

Ke¹,

Li²,

Xu³

et al. 2013

Journal of Endocrinology

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The efficacy of gliquidone for the treatment of diabetic nephropathy was investigated by implanting micro-osmotic pumps containing gliquidone into the abdominal cavities of Goto-Kakizaki (GK) rats with diabetic nephropathy. Blood glucose, 24 h urinary protein, and 24 h urinary albumin levels were measured weekly. After 4 weeks of gliquidone therapy, pathological changes in the glomerular basement membrane (GBM) were examined using an electron microscope. Real-time PCR, western blotting, and immunohistochemistry were employed to detect glomerular expression of receptors for advanced glycation end products (RAGE) (AGER), protein kinase C b (PKCb), and protein kinase A (PKA) as well as tubular expression of the albumin reabsorption-associated proteins: megalin and cubilin. Human proximal tubular epithelial cells (HK-2 cells) were used to analyze the effects of gliquidone and advanced glycation end products (AGEs) on the expression of megalin and cubilin and on the absorption of albumin. Gliquidone lowered blood glucose, 24 h urinary protein, and 24 h urinary albumin levels in GK rats with diabetic nephropathy. The level of plasma C-peptide increased markedly and GBM and podocyte lesions improved dramatically after gliquidone treatment. Glomerular expression of RAGE and PKCb decreased after gliquidone treatment, while PKA expression increased. AGEs markedly suppressed the expression of megalin and cubulin and the absorption of albumin in HK-2 cells in vitro, whereas the expression of megalin and cubilin and the absorption of albumin were all increased in these cells after gliquidone treatment. In conclusion, gliquidone treatment effectively reduced urinary protein in GK rats with diabetic nephropathy by improving glomerular lesions and promoting tubular reabsorption.

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The role of tubular injury in diabetic nephropathy

Cited by 96 publications

References 69 publications

Aquaporin 11 variant associates with kidney disease in type 2 diabetic patients

Aquaporin 11 variant associates with kidney disease in type 2 diabetic patients

Endogenous Fructose Production and Fructokinase Activation Mediate Renal Injury in Diabetic Nephropathy

Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats

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