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. 2016 Apr;89(4):809-22.
doi: 10.1016/j.kint.2015.12.043.

Antagonism of Scavenger Receptor CD36 by 5A Peptide Prevents Chronic Kidney Disease Progression in Mice Independent of Blood Pressure Regulation

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Free PMC article

Antagonism of Scavenger Receptor CD36 by 5A Peptide Prevents Chronic Kidney Disease Progression in Mice Independent of Blood Pressure Regulation

Ana Carolina P Souza et al. Kidney Int. .
Free PMC article

Abstract

Scavenger receptor CD36 participates in lipid metabolism and inflammatory pathways important for cardiovascular disease and chronic kidney disease (CKD). Few pharmacological agents are available to slow the progression of CKD. However, apolipoprotein A-I-mimetic peptide 5A antagonizes CD36 in vitro. To test the efficacy of 5A, and to test the role of CD36 during CKD, we compared wild-type to CD36 knockout mice and wild-type mice treated with 5A, in a progressive CKD model that resembles human disease. Knockout and 5A-treated wild-type mice were protected from CKD progression without changes in blood pressure and had reductions in cardiovascular risk surrogate markers that are associated with CKD. Treatment with 5A did not further protect CD36 knockout mice from CKD progression, implicating CD36 as its main site of action. In a separate model of kidney fibrosis, 5A-treated wild-type mice had less macrophage infiltration and interstitial fibrosis. Peptide 5A exerted anti-inflammatory effects in the kidney and decreased renal expression of inflammasome genes. Thus, CD36 is a new therapeutic target for CKD and its associated cardiovascular risk factors. Peptide 5A may be a promising new agent to slow CKD progression.

Keywords: albuminuria; glomerulosclerosis; inflammasome; inflammation; interstitial fibrosis; remnant kidney model; telemetry.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1. Competition of CD36 ligands with Alexa-Fluor-488 oxLDL binding to CD36-overexpressing HeLa cells and CD36 antagonism by 5A peptide in vitro
Cells were incubated with 2 nM Alexa-Fluor-488 oxLDL with indicated concentrations of unlabeled competitors (X-axis) for 2 h at 37 °C. Unlabeled oxLDL was used as a control. Cell-associated fluorescence was measured by a plate reader.
Figure 2
Figure 2. Effects of CD36KO and 5A peptide therapy on CKD progression
After 4 weeks, untreated WT mice subjected to 5/6Nx+AngII had increased levels of BUN (a) and serum creatinine (b), and (c) urinary albumin-to-creatinine ratio (ACR). These changes were reduced in KO and 5A-treated WT mice [(N=11–19/group; ANOVA with Dunnett's post-hoc test for a–d; N=11–19/group for e, mixed-model analysis (see Experimental Procedures)].
Figure 3
Figure 3. Effects of CD36KO and 5A peptide therapy on renal histology
After 4 weeks, untreated WT mice subjected to 5/6Nx+AngII had increased glomerulosclerosis (a) and interstitial fibrosis (b) scores. These changes were reduced in KO and 5A-treated WT mice. On the right, representative pictures at high-power field HPF (400×). [(N=11–19/group; ANOVA with Dunnett's post-hoc test for a–d; N=11–19/group).
Figure 4
Figure 4. Effects of CD36KO and 5A peptide therapy on metabolic and electrolyte abnormalities associated with CKD
Four weeks after 5/6Nx+AngII, WT mice had typical metabolic and electrolyte changes associated with CKD, which were prevented in CD36KO and 5A-treated WT mice. 5A did not cause liver toxicity. WT mice subjected to 5/6Nx+AngII had very high serum FGF-23 and intact PTH levels, which were significantly lower in CD36KO mice. (N=8–10/group; ANOVA with Dunnett's post-hoc test for a–i; N=6–13/group; ANOVA with Dunnett's post-hoc test for j and k).
Figure 5
Figure 5. Effects of CKD and CK36KO on telemetry blood pressure
WT and CD36KO mice (N=6/group) were subjected to 5/6Nx+AngII and telemetry. Model-based weekly mean values: systolic (a), diastolic (b), and mean arterial blood (c) pressures (Y-axis) significantly increased over time (X-axis), from baseline to 4 weeks, p<0.001, in both groups, without statistical differences between the groups.
Figure 6
Figure 6. Effects of 5a on renal mRNA expression of cytokines and NLRP3 on the progressive CKD model
Four weeks after 5/6Nx+AngII renal mRNA expression of IL-6 (a), CXCL-1 (b), Il-1β (e) and NLRP3 (f) in WT mice treated with 5A was significantly decreased in comparison to non-treated mice. (N=4–6 /group; ANOVA with Dunnett's post-hoc test).
Figure 7
Figure 7. Relationship between CD36 receptor and 5A in the progressive CKD model
Four weeks after 5/6Nx+AngII, CD36 KO mice that received 5A (5mg/kg/day) did not have better renal outcomes as analyzed by serum BUN and creatinine, renal histology, and albumin-to-creatinine ratio in urine in comparison to CD36 KO subjected to the same model without 5A infusion. (N=4–6 /group; ANOVA with Dunnett's post-hoc test).
Figure 8
Figure 8. Effects of 5A therapy on kidney fibrosis, macrophage infiltration (F4/80+ cells) in the UUO model
Ten days after UUO, untreated WT CD-1 mice had substantial cortical thinning (a), interstitial fibrosis (b), and macrophage infiltration of the obstructed kidney (c); 5A-treated mice (15 mg/kg/day) were protected. (d and e) Representative pictures of obstructed kidney sections stained with Masson`s-trichrome from all groups demonstrating increased cortical thinning (d; 1.5×), and interstitial fibrosis (e; 400×) in the untreated UUO group. (N=8 /group; ANOVA with Dunnett’s post-hoc test).
Figure 9
Figure 9. Effects of 5A therapy on renal mRNA expression of cytokines and NLRP3 in the UUO model
Renal mRNA expression of cytokines and inflammasome-associated genes. TGF-β and IL-1β gene expression are decreased in the 5A 15 group. (N=4 /group; ANOVA with Dunnett’s post-hoc test).

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