BIGH3: Role in renal fibrosis

Renal fibrosis, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the final common manifestation of a wide variety of chronic kidney diseases (CKD). The pathogenesis of renal fibrosis is a progressive process that ultimately leads to end-stage renal failure, a devastating disorder that requires dialysis or kidney transplantation. Renal fibrosis is characterized by hypertrophy of both glomerular and tubular elements, progressive accumulation of extracellular matrix components in the glomerular mesangium, and thickening of the glomerular and tubular basement membranes. Transforming Growth Factor Beta Induced Gene Human Clone 3 (BIGH3), an ECM molecule is overexpressed in human diabetic mellitus type 2 (DMT2) kidney cortex. Earlier studies have shown that human DMT2 kidney cortex showed a 10-fold increase in BIGH3 expression when compared to a similarly aged non-diabetic kidney cortex. Papers have demonstrated that TGFbeta is a key mediator in renal fibrosis indicating possible role of BIGH3 upregulation by TGFbeta-1. Previous studies have demonstrated that BIGH3 binds to collagen type I with high affinity and also modulates the self-assembly processes of collagen type I. We hypothesize that BIGH3 in deposition in kidney is associated with collagen type I and fibronectin creating a macro molecular complex promoting fibrosis. Continuous deposition of ECM molecules results in fibrous scars and distorts the fine architecture of kidney tissues, leading to the collapse of renal parenchyma and the loss of kidney function. This study shows that BIGH3 is overexpressed in human DMT2 kidney cortex (p<0.05) and that BIGH3 interacts with collagen type I and fibronectin in vivo and possibly promotes matrix aggregation. Data also indicated that displacement of native BIGH3 in the aggregates by recombinant BIGH3 might give us possible insight into the therapeutic approach towards finding treatment for renal fibrosis. In summary, this study suggests BIGH3 plays a role in renal fibrosis. Therefore, BIGH3 may be an attractive target as an intervention between diabetic complications and the kidney.