Diabetic nephropathy is characterized by albuminuria/proteinuria, and over-reabsorption of protein/albumin triggers tubulointerstitial inflammation and fibrosis. The goal of the proposed studies is to uncover the molecular mechanism(s) involved in albumin overload-related renal injury in progressive diabetic nephropathy. Tubular Kidney injury molecule-1 (KIM-1) induction was associated with increased MMP-9, myofibroblast activation and albuminuria/proteinuria in diabetic rats. The pilot study revealed that FITC-albumin was preferentially accumulated in KIM-1-expressing tubular cells. Therefore, the central hypothesis is that Tubular KIM-1 expression exacerbates diabetic renal injury by enhancing protein overload-induced tubulointerstitial inflammation and fibrosis.
Aim I will test the hypothesis that tubule-specific overexpression of KIM-1 exacerbates diabetic renal injury. Systematic studies will be conducted 1) to characterize the spatial, temporal, and quantitative expression of human KIM-1 in doxycycline-inducible Pax8- rtTA/hKIM1 transgenic mice and 2) to determine if tubule-specific expression of hKIM-1 promotes renal injury in high-fat diet and streptozotocin-induced diabetic mice.
Aim II will test the hypothesis that KIM-1 expression enhances protein overload-induced proinflamatory and profibrotic responses in renal tubular epithelial cells. Proposed studies aim 1) to define the correlations among tubular KIM-1 expression, protein reabsorption, and tubular cells activation in the kidneys of Pax8-rtTA/hKIM1 transgenic mice and 2) to examine the effects of KIM-1 expression on tubular proinflammatory and profibrotic responses to albumin, high glucose, and TGF-?1 stimulation in cultured tubular epithelial cells.
Aim III will test the hypothesis that inhibition of KIM-1 would prevent protein overload and attenuate diabetic tubulointerstitial damage. Both in vitro and in vivo studies are proposed 1) to examine if inhibiting KIM-1 by neutralizing antibodies or shRNA gene silencers would prevent albumin overload-induced tubular cell activation and injury in cultured tubular epithelial cells and 2) to define if inhibiting KIM-1 expression and activity would prevent excess protein reabsorption by proximal tubular cells and attenuate tubulointerstitial injury in the diabetic kidneys.
Diabetic nephropathy is the most common cause of end-stage renal disease. Proteinuria and tubular cell injury are important mechanisms for disease progression. The proposed research will enable us to establish new therapeutic strategies to prevent and treat diabetic kidney disease in humans by examining the role of kidney injury molecule-1 (KIM-1) in the pathogenesis of tubular injury and dysfunction in diabetes.
| Zhao, Xueying; Chen, Xiaoming; Chima, Ashmeer et al. (2018) Albumin induces CD44 expression in glomerular parietal epithelial cells by activating extracellular signal-regulated kinase 1/2 pathway. J Cell Physiol : |
| Chen, Xiaoming; Cobbs, Alyssa; George, Jasmine et al. (2017) Endocytosis of Albumin Induces Matrix Metalloproteinase-9 by Activating the ERK Signaling Pathway in Renal Tubule Epithelial Cells. Int J Mol Sci 18: |
