Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF₁Rats

Abstract

Our previous studies indicate that prolonged caffeine consumption exacerbates renal failure in nephropathy associated with the metabolic syndrome. Reduced activity of the antioxidant defense system and beneficial effects of antioxidant therapy have been reported in diabetic rats and humans. The purpose of this study was to examine the early renal effects of caffeine consumption and the effects of concomitant antioxidant therapy in young obese, diabetic ZSF1 rats. Eleven-week-old male ZSF1 rats were randomized to drink tap water, caffeine (0.1%), tempol (1 mmol/ L), or a solution containing caffeine and tempol for nine weeks. Caffeine significantly reduced body weight and glycosuria (weeks 2-9), improved glucose tolerance (week 9), had no effect on elevated plasma triglycerides, plasma cholesterol (week 9) and blood pressure (week 9), and significantly increased plasma cholesterol level (weeks 5 and 9). Yet, as early as after two weeks, caffeine greatly augmented proteinuria and increased renal vascular resistance (RVR) and heart rate (HR: week 9). Tempol had no effects on metabolic status and development of proteinuria, did not alter caffeine-induced metabolic changes and early proteinuria, and attenuated caffeine-induced increase in HR and RVR. Immunohistochemical analysis revealed significant glomerular and interstitial inflammation, proliferation, and fibrosis in control animals. Caffeine augmented the influx of glomerular and interstitial macrophages (ED1+ cells) influx, glomerular and tubular proliferative response, and glomerular collagen IV content. Tempol abolished the exacerbation of renal inflammation, proliferation, and fibrosis induced by caffeine. In conclusion, in nephropathy associated with the metabolic syndrome, caffeine-most likely through the interaction with adenosine receptors and interference with anti-inflammatory and/or glomerular hemodynamic effects of adenosine-augments proteinuria and stimulates some of the key proliferative mechanisms involved in glomerular remodeling and sclerosis. Tempol does not prevent early renal injury (i.e., proteinuria) induced by caffeine, yet abolishes late renal inflammatory, proliferative, and fibrotic change induced by chronic caffeine consumption in obese ZSF1 rats.

Coffee, nutritional status, and renal artery resistive index

“…40 The conceptual view of CKD treatment at an early stage can take also advantage of the clinical nutritional information of this study. We envisage that approaches addressed at the change of lifestyle/environmental factors could be favorable for renal artery responsiveness under relatively stressful conditions, for example, in arterial hypertension and in conditions with increased pulse pressure.…”

“…37 Long-term consumption of beverages containing caffeine such as coffee and green tea is associated with a reduced risk of type 2 diabetes mellitus; in healthy subjects daily caffeine intake reduces insulin sensitivity 38 ; the vascular repair mechanism is adequately functional in the early stage of CKD. 39,40 In experimental models, caffeine attenuated the endotoxin-induced release of cytokines and augmented endotoxin-induced increases in plasma catecholamines and PRA: caffeine, most likely through the interaction with adenosine receptors and interference with antiinflammatory and/or glomerular hemodynamic effects of adenosine, augments proteinuria and stimulates some of the key proliferative mechanisms involved in glomerular remodeling and sclerosis. 41 Adenosine is an endogenous nucleoside with potent vasodilatory capacities: its mechanisms of action, however, remain elusive.…”

Methylxanthines and the Kidney

“…Finally, long-term treatment with caffeine reduced renal function and augmented proteinuria in obese diabetic ZSF1 rats despite improving glucose tolerance. Caffeine-induced renal deterioration was paralleled by enhanced fibrosis, proliferation, and inflammation (Tofovic et al 2002; Tofovic et al 2007). In addition to stimulating the release of renin, the effects of caffeine may be mediated through interference with the direct anti-inflammatory effects of adenosine (Tofovic et al 2007).…”

Daily Intake of Grape Powder Prevents the Progression of Kidney Disease in Obese Type 2 Diabetic ZSF1 Rats

“…A previous study has demonstrated that the kidney disease of these rats is mostly independent on hypertension and/or hypertensive nephropathy [45], suggesting the attribution of renal pathophysiology strictly to other components of MetS, such as obesity and/or hyperglycemia. Indeed, many studies in literature use these rats as an appropriate model for the purposes of investigating MetS-related kidney disease or DN [28,46]. Our data show that the daily intake of WGP had no impact on the bodyweight or obesity of these rats (Figure 1).…”