A microRNA circuit mediates transforming growth factor-β1 autoregulation in renal glomerular mesangial cells

Abstract

Enhanced transforming growth factor-β1 (TGF-β1) expression in renal cells promotes fibrosis and hypertrophy during the progression of diabetic nephropathy. The TGF-β1 promoter is positively controlled by the E-box regulators, Upstream Stimulatory Factors (USFs), in response to diabetic (high glucose) conditions; however, it is not clear whether TGF-β1 is autoregulated by itself. Since changes in microRNAs (miRNAs) have been implicated in kidney disease, we tested their involvement in this process. TGF-β1 levels were found to be upregulated by microRNA-192 (miR-192) or miR-200b/c in mouse mesangial cells. Amounts of miR-200b/c were increased in glomeruli from type 1 (streptozotocin) and type 2 (db/db) diabetic mice, and in mouse mesangial cells treated with TGF-β1 in vitro. Levels of miR-200b/c were also upregulated by miR-192 in the mesangial cells, suggesting that miR-200b/c are downstream of miR-192. Activity of the TGF-β1 promoter was upregulated by TGF-β1 or miR-192, demonstrating that the miR-192-miR-200 cascade induces TGF-β1 expression. TGF-β1 increased the occupancy of activators USF1 and Tfe3, and decreased that of the repressor Zeb1 on the TGF-β1 promoter E-box binding sites. Inhibitors of miR-192 decreased the expression of miR-200b/c, Col1a2, Col4a1 and TGF-β1 in mouse mesangial cells, and in mouse kidney cortex. Thus, miRNA-regulated circuits may amplify TGF-β1 signaling accelerating chronic fibrotic diseases such as diabetic nephropathy.

microRNAs in Diabetic Kidney Disease

“…They show that miR-192 levels increase significantly in glomeruli isolated from streptozotocin-injected diabetic mice as well as diabetic db/db mice, in parallel with increased TGF-1 and collagen 1a2 (Col1a2) levels. Upregulation of renal miR-192 during diabetic kidney diseases is also found in db/db mice, type 2 diabetes rat, and whole blood samples of type 2 diabetes patients [49][50][51][52]. In addition, TGF-1 induces miR-192 levels in both mouse MCs and isolated glomeruli from both type 1 and type 2 mouse models of diabetes [48,52].…”

“…Upregulation of renal miR-192 during diabetic kidney diseases is also found in db/db mice, type 2 diabetes rat, and whole blood samples of type 2 diabetes patients [49][50][51][52]. In addition, TGF-1 induces miR-192 levels in both mouse MCs and isolated glomeruli from both type 1 and type 2 mouse models of diabetes [48,52]. Other studies also show miR-192 upregulation in MCs and TECs after treatment with high glucose, AGE, and TGF-1 [53][54][55].…”

“…However, it is also found that amounts of miR-200b/c are elevated in glomeruli from type 1 (streptozotocin) and type 2 (db/db) diabetic mice and in mouse mesangial cells treated with TGF-1 in vitro [52]. Recently, inducing miR200b and miR-200c and their target FOG2, an inhibitor of phosphatidylinositol 3-kinase activation, is shown to be one of the mechanisms of how TGF-activates Akt in glomerular mesangial cells [90].…”

New-onset diabetes mellitus after renal transplantation

“…miR-216a, miR-217 and key miR-200 family members were increased in mouse kidney glomerular mesangial cells treated with TGF-β and in kidney glomeruli from mouse models of DM (ref. [51][52] ). In addition, miR-192, which is highely expressed in kidney, is upregulated in mouse kidney glomerular mesangial cells treated with TGF-β and renal glomeruli from mouse models of type 1 and type 2 DM relative to the corresponding controls 49 .…”

Drugs for Diabetic Nephropathy- Full Review

“…[95] Drugs that modify TGFβ expression or reduce TGFβ level 1) ACE inhibitor Perindopril reduces intrarenal TGFβ expression and activity [125] 2) ACE inhibitor reduces serum and urinary level of TGFβ [131] 3) Antifibrotic agent N-acetyl-seryl-aspartyl-lysyl-proline reduced extracellular matrix production, prevented fibrosis and albuminuria in mice model. Also additional renoprotection can be offered when combined with angiotensin II receptor antagonist losartan [130,140] www.wjpps.com 2) Several blocking Abs against TGFβ reduce mesangial matrix accumulation and glomerulosclerosis in diabetic mouse model [75,132] 3) TGF-AY1Ab is in clinical development for the treatment of chronic kidney diseases with focus on diabetic nephropathy. [90] DRUGS-Pirfenidone [133] , Tranilast [134,135] , fresolimumab.…”