title: Caffeine augments proteinuria in puromycin-aminonucleoside nephrotic rats.
abstract: Several studies indicate that increased intrarenal adenosine concentrations may attenuate puromycin-aminonucleoside (PAN)-induced nephropathy in rats. The purpose of this study was to investigate the chronic effects of caffeine, a nonselective adenosine receptor antagonist, on renal function and structure in PAN-induced nephropathy. Animals were randomized to receive drinking water or 0.1% caffeine solution. PAN was administered in two doses to a subset from each group at 1 week (100 mg/kg, s.c.; Purom-1) and 15 wks (80 mg/kg, s.c.; Purom-2) after initiating caffeine treatment (PAN and CAFF-PAN groups). The remaining animals served as time controls (CON and CAFF groups). Renal excretory function was followed for 23 wks. Caffeine consumption significantly augmented PAN-induced proteinuria after both PAN injections (Purom-1 and Purom-2, p<0.05 and p<0.001 respectively; CAFF-PAN vs. PAN). In addition, caffeine potentiated the transient reduction in creatinine clearance (CrCl) induced by PAN. Caffeine consumption for 23 wks significantly reduced CrCl in conscious nephrotic animals (4.76 +/- 0.98 vs. 8.51 +/- 1.55 L/kg/day, CAFF-PAN vs. PAN). Seven days after both PAN injections, increased plasma renin activity was detected in animals that were consuming caffeine as compared with corresponding control groups (CAFF and CAFF + PAN vs CON and PAN, respectively). Eight weeks after the second injection of PAN, acute measures of renal hemodynamic and excretory function were compared in anesthetized animals and renal samples were analyzed for histological changes. In PAN-rats, caffeine treatment for 23 weeks significantly reduced inulin clearance (0.28 +/- 0.09 vs. 0.57 +/- 0.12 mL/min/gr kidney. CAFF-PAN vs PAN, p<0.05), tended to increase renal vascular resistance (59.0 +/- 9.5 vs. 42.9 +/- 5.5 mmHg/mL/min/gr kidney, CAFF-PAN vs. PAN, p < 0.06), potentiated the development of more severe tubulointerstitial damage (tubular atrophy, presence of proteinaceous material, tubular dilatation, interstitial inflammation, interstitial fibrosis), and tended to increase glomerulosclerosis. In conclusion, this study indicates that caffeine adversely affects renal function in PAN-nephrotic rats, and that this effect may be due, in part, to increased activity of the renin angiotensin system.
authors.affiliation: Center for Clinical Pharmacology, and Department of Medicine, University of Pittsburgh Medical Center, Pennsylvania 15213-2582, USA. TOFOVIC@MED1.DEPT-MED.pitt.edu
authors.forename: S P
authors.initials: SP
authors.lastname: Tofovic
authors.forename: B R
authors.initials: BR
authors.lastname: Rominski
authors.forename: S
authors.initials: S
authors.lastname: Bastacky
authors.forename: E K
authors.initials: EK
authors.lastname: Jackso
authors.forename: C K
authors.initials: CK
authors.lastname: Kost
mesh_terms: D000818:Animals; D002110:Caffeine / Q000633:toxicity*; D003404:Creatinine / Q000378:metabolism; D018450:Disease Progression; D004357:Drug Synergism; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D009401:Nephrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D011507:Proteinuria / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D058915:Purinergic P1 Receptor Antagonists; D011692:Puromycin Aminonucleoside / Q000633:toxicity*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood
chemical_list: D010726:Phosphodiesterase Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D002110:Caffeine; D011692:Puromycin Aminonucleoside; D003404:Creatinine; D012083:Renin