Tracking the Elusive Fibrocyte and Serum Biomarkers in Hypertensive and Diabetic Kidney Fibrosis---A Therapeutic Approach with Celastrol

Not only common in end-stage renal pathological changes, renal fibrosis is considered to be a common terminal point of various types of renal disease. To date, it is unclear whether there is a causal relationship between fibrosis and chronic kidney disease (CKD) and whether fibrosis contributes to the development of CKD. However, the extent of tubulointerstitial disease is the single best determinant of decline of kidney function; thus, renal tubulointerstitial fibrosis is widely regarded as the common pathway of progressive CKD. To develop effective antifibrotic drugs to slow progression or even reverse chronic kidney injury will be very important currently and in the foreseeable future. Fibrocytes are defined as collagen-producing cells of hematopoietic origin. Although considering the limitations in detecting fibrocytes described in the literature, a large number of data suggest that fibrocytes contribute to renal fibrosis, either directly by production of ECM or indirectly by supporting the expansion and matrix production of resident cells in the kidney. Identifying interference with fibrocytes or fibrocyte function is important in understanding their role in renal disease. Based on our preliminary results that celastrol, a triterpene from plants has been used in traditional oriental medicine to treat neoplastic and autoimmune diseases, exerts potent antifibrotic effects in a unilateral ureteral ligation (UUO) kidney fibrotic animal model. In this study, we will investigate the therapeutic effects of celastrol in hypertension and diabetes induced kidney fibrosis in two transgenic mice models (renin-transgenic mice, RenTg and dbNOS double knockout mice, eNOS-/- db/db). A combination treatment regimen with celastrol and irbesartan (a extensively clinical used kidney protective medication) will also be examined in this study. A systemic experimental results collection, including: animal physical data(body weight, blood pressure, urine amount), biochemical parameters (serum creatinine, urine protein, urine MCP-1 concentration), kidney fibrosis score (IHC stain, Trichrome stain, fibrosis & inflammation molecule Q-PCR of TNFα / iL6 / TGF-β / PDGF / αSMA / Collgen I ), serum cytokine panel (ELISA Cytokine Array), and fibrocyte determination (amount and character of circulating and kidney isolated fibrocyte), will be thoroughly performed to build up a Molecular Bio-Patho-Medical information data base. We believe that this study will provide significant results shown the therapeutic effects of celastrol in reducing kidney fibrosis. Also, a biomarker-stratified antifibrotic therapy, possibly through a combination treatment regimen will be translated to clinical medicine in the future.

Project ID:PC10408-2202
External Project ID:MOST104-2314-B182A-149