Tauroursodeoxycholic Acid (TUDCA) Prevents High Salt‐Induced, ETB Dysfunction‐ Dependent Renal Cortical Injury
Authors: De Miguel Carmen , Kasztan Malgorzata , Lever Jeremie M. , Carmines Pamela K. , Pollock David M. , Pollock Jennifer S. 
Published: June 2021

Chronic high salt intake exaggerates renal injury and inflammation, especially with the loss of functional endothelin B (ETB) receptors. We recently found that treatment with the chemical chaperone tauroursodeoxycholic acid (TUDCA) prevents chronic high salt‐induced renal injury in the ETB deficient (ETB def) rat. After 3 weeks of high salt diet (HSD, 8% NaCl), ETB def rats displayed glomerular and cortical tubular damage, as indicated by exaggerated proteinuria, albuminuria, KIM‐1 excretion, glomerulosclerosis, glomerular capsule thickness, cortical interstitial fibrosis, brush border damage and increased iron deposition in the proximal tubules. Treatment with TUDCA (400 mg/kg/day, i.p.) during the HSD period significantly prevented these signs of kidney injury and increased expression of the endocytic receptor megalin in the proximal tubule (vehicle vs. TUDCA: 11.3 ± 0.5% vs. 15.8 ± 0.8% area stained positive; p<0.05; n = 5–8/group). However, the mechanisms by which TUDCA protects the kidney remain unknown. The present studies were designed to determine the effects of TUDCA on glomerular permeability and cortical immune cell infiltration. 10 week‐old male Wistar Kyoto rats were fed HSD, treated with the ETB receptor antagonist A‐192126 (10mg/Kg/day, drinking water) and received daily injections of TUDCA or vehicle for 3 weeks. At the end of the studies, kidneys were collected and glomeruli and cortical immune cells were isolated for assessment of glomerular permeability to albumin (Palb) and immune cell phenotype. Pharmacological blockade of the ETB receptor during HSD resulted in significantly elevated Palb in vehicle‐treated rats compared to TUDCA‐treated rats (0.38 ± 0.03 vs. 0.15 ± 0.02; p<0.05; n = 5/group). Cortical immune cell evaluation by flow cytometry demonstrated no effects of TUDCA on mononuclear phagocytes or CD45+ leukocyte populations. However, TUDCA treatment resulted in significantly less T cells in the cortex compared to vehicle‐treated rats (% total events CD3+ cells, vehicle vs. TUDCA: 0.28 ± 0.04 vs. 0.18 ± 0.03; p<0.05; n = 5/group). Further, the effects of TUDCA on cortical T cell populations were specific to CD4+ cells (% total events CD3+ CD4+ cells: 0.13 ± 0.02 vs. 0.08 ± 0.00; p<0.05; n = 5/group), as CD3+ CD8+ cell percentages were similar between groups. In conclusion, TUDCA minimizes the detrimental effects of HSD consumption on the glomerular filtration barrier and specifically decreases CD4+ inflammation in the renal cortex. These results highlight the potential use of TUDCA as a preventive tool against chronic high salt‐induced renal damage especially when ETB receptors are dysfunctional.

Support or Funding Information

Funded by NIH P01 HL136267‐01S1 to CDM and P01 HL69999, P01HL136267, AHA SFRN 24450002 and U01HL117684 to DMP and JSP.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.