Pirfenidone Is Renoprotective in Diabetic Kidney Disease

Abstract

Although several interventions slow the progression of diabetic nephropathy, current therapies do not halt progression completely. Recent preclinical studies suggested that pirfenidone (PFD) prevents fibrosis in various diseases, but the mechanisms underlying its antifibrotic action are incompletely understood. Here, we evaluated the role of PFD in regulation of the extracellular matrix. In mouse mesangial cells, PFD decreased TGF-␤ promoter activity, reduced TGF-␤ protein secretion, and inhibited TGF-␤-induced Smad2-phosphorylation, 3TP-lux promoter activity, and generation of reactive oxygen species. To explore the therapeutic potential of PFD, we administered PFD to 17-wk-old db/db mice for 4 wk. PFD treatment significantly reduced mesangial matrix expansion and expression of renal matrix genes but did not affect albuminuria. Using liquid chromatography with subsequent electrospray ionization tandem mass spectrometry, we identified 21 proteins unique to PFD-treated diabetic kidneys. Analysis of gene ontology and protein-protein interactions of these proteins suggested that PFD may regulate RNA processing. Immunoblotting demonstrated that PFD promotes dosage-dependent dephosphorylation of eukaryotic initiation factor, potentially inhibiting translation of mRNA. In conclusion, PFD is renoprotective in diabetic kidney disease and may exert its antifibrotic effects, in part, via inhibiting RNA processing.

Renoprotective mechanisms of pirfenidone in hypertension-induced renal injury: through anti-fibrotic and anti-oxidative stress pathways

“…TGFβ also activates Smad-independent signaling sions of renal TGFβ compared to the Control group. TGFβ activates a unique signal transduction pathway that acts via the Smad family of proteins (9,27). In the present study, PFD treatment did not affect the protein expression of total Smad2/3 (Fig.…”

“…PFD was reported to have exhibited anti-oxidative stress effects in mesangial cells and in a cirrhosis model (27,30). In the present study, a total antioxi-…”

“…Recent reports also indicate that TGFβ and its downstream Smad pathway play important roles in renal diseases (4,26,31). In particular, PFD inhibits total Smad2/3 protein expression and TGFβ-induced Smad2 phosphorylation in murine mesangial cells (27). The balance between MMPs and TIMPs is also influenced by TGFβ in the kidneys (8,10,25).…”

“…PFD has been considered as an antagonist of transforming growth factor β (TGFβ), and has anti-fibrotic, anti-inflammatory, and antioxidative stress activities (6, 12-14, 27, 36). PFD has demonstrated an anti-fibrotic effect via the downregulation of TGFβ expression in several animal nephropathy models, including unilateral ureteral obstruction (36), diabetic nephropathy (24,27), nephrectomy (35,38), vanadate-induced renal fibrosis (1), and calcineurin inhibitor-induced nephrotoxicity (5,6,34). In addition, the clinical effectiveness of PFD has been evaluated in human diabetic nephropathy (32) and focal segmental glomerulosclerosis (7).…”

“…Oxidative stress is related to progressive renal injury (28). PFD is reported to exert antioxidative stress in mesangial cells and in a cirrhosis model (27,30). Therefore, the anti-inflammatory and anti-oxidative stress effects of PFD are also expected to ameliorate renal injury.…”