Abstract
Diabetic nephropathy is increasingly recognized as a major contributor to kidney failure in patients with obesity and type 2 diabetes. This study was designed to identify the molecular mediators of kidney injury associated with metabolic syndrome with or without hyperglycemia. We compared renal gene expression profiles in Zucker lean (ZL), Zucker obese (ZO), and Zucker diabetic (ZD) rats using cDNA microarray with quantitative verification of selected transcripts by real-time PCR. Compared to the 20-week-old ZL control (glucose: 110 ± 8 mg/dL), both prediabetic ZO (glucose: 157 ± 11 mg/dL) and diabetic ZD (glucose: 481 ± 37 mg/dL) rats displayed hyperlipidemia and kidney injury with a high degree of proteinuria. cDNA microarray identified 25 inflammation and injury-related transcriptomes whose expression levels were similarly increased in ZO and ZD kidneys. Among them, kidney injury molecule-1 (KIM-1) was found to be the most highly upregulated in both ZO and ZD kidneys. Immunofluorescence staining of kidney sections revealed a strong correlation between lipid overload and KIM-1 upregulation in proximal tubules of ZO and ZD rats. In cultured primary renal tubular epithelial cells (TECs), administration of saturated fatty acid palmitate resulted in an upregulation of KIM-1, osteopontin, and CD44, which was greatly attenuated by U0126, an inhibitor of extracellular signal-regulated kinase (ERK)1/2. Moreover, knockdown of KIM-1 by siRNA interference inhibited palmitate-induced cleaved caspase-3, osteopontin, and CD44 proteins in primary TECs. Our results indicate that KIM-1 expression is upregulated in renal lipotoxicity and may play an important role in fatty acid-induced inflammation and tubular cell damage in obesity and diabetic kidney disease.
Highlights
Obesity and type 2 diabetes affect one third of adults in the United States and are the leading causes of end-stage renal disease
Blood glucose was only slightly increased in the Zucker obese (ZO) rats, whereas blood glucose was greatly elevated in Zucker diabetic (ZD) rats (Figure 1B)
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Summary
Obesity and type 2 diabetes affect one third of adults in the United States and are the leading causes of end-stage renal disease. Obesity and diabetes-related nephropathy manifest as a clinical syndrome consisting of albuminuria, progressive decline in renal function, and an increased risk for cardiovascular disease [1]. A minimum amount of albumin-bound FAs is filtered through glomeruli and reabsorbed into the proximal tubules [5,6,7]. In albuminuric/proteinuric kidney disease, the damaged glomerulus allows albumin-bound FAs to be filtered and gain access to the previously unexposed proximal tubule luminal surface, where aberrant FA reabsorption could occur. Excess FAs overload the proximal tubular cells, aggravating urinary protein-related tubulointerstitial damage. The exact mediator(s) responsible for FA-induced tubulointerstitial inflammation and renal dysfunction remain largely unknown
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