CD36 Regulates Oxidative Stress and Inflammation in Hypercholesterolemic CKD

Scavenger receptors play a central role in atherosclerosis by processing oxidized lipoproteins and mediating their cellular effects. Recent studies suggested that the atherogenic state correlates with progression of chronic kidney disease (CKD); therefore, scavenger receptors are candidate mediators of renal fibrogenesis. Here, we investigated the role of CD36, a class B scavenger receptor, in a hypercholesterolemic model of CKD. We placed CD36-deficient mice and wild-type male mice on a high-fat Western diet for 7 to 8 wk and then performed either sham or unilateral ureteral obstruction surgery. CD36-deficient mice developed significantly less fibrosis compared with wild-type mice at days 3, 7, and 14 after obstruction. Compared with wild-type mice, CD36-deficient mice had significantly more interstitial macrophages at 7 d but not at 14 d. CD36-deficient mice exhibited reduced levels of activated NF-κB and oxidative stress (assessed by measuring fatty acid–derived hydroxyoctadecadienoic acid and protein carbonyl content) and decreased accumulation of interstitial myofibroblasts compared with wild-type mice. These data suggest that CD36 is a key modulator of proinflammatory and oxidative pathways that promote fibrogenesis in CKD

Interstitial fibrosis in mice with overload proteinuria: Deficiency of TIMP-1 is not protective

Background. Progressive renal interstitial fibrosis is characterized by up-regulated expression of the gene that encodes the tissue inhibitor of metalloproteinases-1 (TIMP-1), a regulator of extracellular matrix remodeling, suggesting that impaired matrix turnover contributes to the fibrogenic process. The present study was designed to develop a murine model of renal interstitial fibrosis, and to determine the functional significance of up-regulated Timp-1 expression by comparing the severity of this renal disease in wild-type mice and mice genetically deficient in Timp-1. Methods. Initial pilot studies developed and characterized a murine model of bovine serum albumin (BSA)-induced protein-overload proteinuria with respect to the degree of proteinuria, severity of interstitial fibrosis, and renal mRNA levels for genes encoding matrix proteins, transforming growth factor-β1 (TGF-β1), and TIMP-1, -2, -3, and -4. In the final study, the severity of interstitial fibrosis was compared in wild-type and Timp-1-deficient mice after six weeks of proteinuria. Results. Mice injected with large daily intraperitoneal doses of BSA developed proteinuria, interstitial inflammation, and progressive interstitial fibrosis. A time course study based on measurements after one, two, and six weeks of BSA injections showed increased renal mRNA levels for the matrix genes procollagens α1(I), α1(III), and α2(IV) and TGF-β1 and Timp-1. Timp-2 and Timp-3 genes were constitutively expressed at high levels in the normal kidneys and showed little change in the proteinuric kidneys. Timp-4 transcripts were not detected in any of the kidneys. After six weeks of BSA overload-proteinuria, the groups (N = 8 per group) of wild-type and Timp-1-deficient mice developed significant interstitial fibrosis compared with the control saline-injected groups. The severity of the interstitial fibrosis was similar in both proteinuric groups based on an assessment of the final kidney weight, total kidney collagen content, and the number of interstitial fields with increased fibronectin staining. Conclusions. Results of the present study indicate that TIMP-1 deficiency does not alter the degree of interstitial fibrosis in the murine overload proteinuria model. Potential explanations include Timp-1 genetic redundancy, as suggested by the observation that, despite significant intrarenal induction of the Timp-1 gene expression, net renal metalloproteinase-9 (MMP-9) activity was not significantly altered. TIMP-1 is a multifunctional protein that may play a metalloproteinase-independent role in response to renal injury.link_to_subscribed_fulltex

Vitronectin accumulates in the interstitium but minimally impacts fibrogenesis in experimental chronic kidney disease

Vitronectin (Vtn) is a glycoprotein found in normal serum and pathological extracellular matrix. Given its known interactions with plasminogen activator inhibitor-1 (PAI-1) and Vtn cellular receptors, especially αvβ3 integrin and the urokinase receptor (uPAR), this study was designed to investigate its role in renal fibrogenesis in the mouse model of unilateral ureteral obstruction (UUO). Kidney Vtn mRNA levels were increased ×1.8–5.1 and Vtn protein levels ×1.9–3 on days 7, 14, and 21 after UUO compared with sham kidney levels. Groups of age-matched C57BL/6 wild-type (Vtn+/+) and Vtn−/− mice (n = 10–11/group) were killed 7, 14, or 21 days after UUO. Absence of Vtn resulted in the following significant differences, but only on day 14: fewer αSMA+ interstitial myofibroblasts (×0.53), lower procollagen III mRNA levels (×0.41), lower PAI-1 protein (×0.23), higher uPA activity (×1.1), and lower αv protein (×0.32). The number of CD68+ macrophages did not differ between the genotypes. Despite these transient differences on day 14, the absence of Vtn had no effect on fibrosis severity based on both picrosirius red-positive interstitial area and total kidney collagen measured by the hydroxyproline assay. These findings suggest that despite significant interstitial Vtn deposition in the UUO model of chronic kidney disease, its fibrogenic role is either nonessential or redundant. These data are remarkable given Vtn's strong affinity for the potent fibrogenic molecule PAI-1