Renal Endocannabinoid Dysregulation in Obesity-Induced Chronic Kidney Disease in Humans

Abstract

The endocannabinoid system (ECS) regulates various physiological processes, including energy homeostasis and kidney function. ECS upregulation in obese animals and humans suggests a potential link to obesity-induced chronic kidney disease (CKD). However, obesity-induced ECS changes in the kidney are mainly studied in rodents, leaving the impact on obese humans unknown. In this study, a total of 21 lean and obese males (38-71 years) underwent a kidney biopsy. Biochemical analysis, histology, and endocannabinoid (eCB) assessment were performed on kidney tissue and blood samples. Correlations between different parameters were evaluated using a comprehensive matrix. The obese group exhibited kidney damage, reflected in morphological changes, and elevated kidney injury and fibrotic markers. While serum eCB levels were similar between the lean and obese groups, kidney eCB analysis revealed higher anandamide in obese patients. Obese individuals also exhibited reduced expression of cannabinoid-1 receptor (CB1R) in the kidney, along with increased activity of eCB synthesizing and degrading enzymes. Correlation analysis highlighted connections between renal eCBs, kidney injury markers, obesity, and related pathologies. In summary, this study investigates obesity's impact on renal eCB "tone" in humans, providing insights into the ECS's role in obesity-induced CKD. Our findings enhance the understanding of the intricate interplay among obesity, the ECS, and kidney function.

Keywords: chronic kidney disease; endocannabinoid system; obesity.

Figure A1

Kidney inflammation and fibrosis gene expression in lean vs. obese individuals. Relative quantification of mRNA levels of TNFα, IL-6, IP-10, TIMP1, FN, and COL1 genes. Data are mean ± SD.

Figure 1

Kidney pathology of lean vs. obese individuals. (A) Representative images of ×20 magnified H&E-stained kidneys. Quantification of glomerular area (B) and Bowman’s space area (C). Kidney injury marker-1 (KIM-1) was measured via Western blot and quantified (D,E). TGFB and IL-18 relative kidney mRNA expression (F). Representative images of ×20 magnified Trichrome-stained kidney sections (G) and fibrosis quantification (H). Data are mean ± SD; * p < 0.05 obese vs. lean group.

Figure 2

Serum and kidney eCB levels in lean vs. obese patients. 2-AG (A), AEA (B), PEA (C), OEA (D), and AA (E) levels were extracted from serum, and 2-AG (F), AEA (G), PEA (H), OEA (I), and AA (J) levels were extracted from kidney tissue. All eCBs were measured using LC-MS/MS. Data are mean ± SD; * p < 0.05 vs. lean group.

Figure 3

Kidney CB1R and ECS enzyme expression levels. Kidney proteins were extracted; CB1R (A) and FAAH (B) levels were examined via Western blot and quantified. Relative mRNA expression of FAAH, NAPEPLD, DAGLA, DAGLB, and MGLL genes (C). Data are mean ± SD; * p < 0.05 vs. lean group.

Figure 4

Large-scale correlation analysis. This correlation matrix displays the Pearson correlation coefficients between multiple variables. The matrix was applied to variables of all patients (A) and then stratified according to their BMI, analyzing the lean (B) and obese (C) groups separately. In eCBs measurements, K = kidney, and S = serum.