Increased renal collagen cross‐linking and lipid accumulation in nephropathy of Zucker diabetic fatty rats

Abstract

Zucker diabetic fatty (ZDF) rat is a genetic model of type 2 diabetes and obesity. The mechanism underlying nephropathy in ZDF rats, however, remains unclear. ZDF rats were compared to age-matched Zucker lean (ZL) rats. Physiological and blood biochemical parameters, renal glomerular cross-sectional area (hematoxylin-eosin staining), fibrosis (van Giesen staining), collagen composition (Sircol Collagen Assay), lipids (enzymatic method) and mRNA expression (RT-PCR) were determined. ZDF rats showed an increase in renal-insoluble collagen content and the ratio of renal-insoluble to salt-soluble collagen (2- and 1.5-fold of the control animals). There were increases in renal glomerulosclerosis and interstitial fibrosis in ZDF rats (increased to 2-fold) in the glomerular mesangium and tubulointerstitium, and increased glomerular area. Renal triglyceride accumulated to greater than 2-fold of those levels in ZL rats. These changes were accompanied by hypoalbuminemia, and elevated plasma blood urea nitrogen and uric acid levels. Gene profiling showed increased expression of transcripts encoding the glomerulosclerotic mediator collagens I and IV, plasminogen activator inhibitor-1, transforming growth factor-beta1, and angiotensin II type 1 receptor in ZDF rat kidney. Moreover, renal expression of mRNAs encoding sterol regulatory element-binding protein-1, a nuclear transcription factor that activates genes involved in fatty acid synthesis, and acetyl-CoA carboxylase, a key enzyme that mediates fatty acid synthesis, was increased in ZDF rats. Our findings suggest that dysregulated gene expression may result in increased renal collagen cross-linking and lipid accumulation, that may be associated with development of nephropathy in the animal model of type 2 diabetes and obesity.