Kinins are involved in the antiproteinuric effect of angiotensin-converting enzyme inhibition in experimental diabetic nephropathy.
The present study examined non-insulin-treated streptozotocin (STZ)-induced diabetic rats to determine the role of kinins in diabetic nephropathy. Their involvement in the renoprotective effect of the angiotensin-converting enzyme inhibitor (ACEI) ramipril was investigated using the bradykinin (BK) B(2)-receptor antagonist, icatibant (HOE 140), or a combination of the two drugs.Although, none of the treatments prevented the decline of the glomerular filtration rate (GFR) in diabetic rats, ramipril (3 mg/kg/day), but not icatibant (HOE 140; 500 microg/kg/day), prevented proteinuria in these animals. However, the antiproteinuric effect of ramipril was reduced by 45% when combined with icatibant. To explore whether the renal kallikrein-kinin system (KKS) belongs to the underlying mechanisms of these findings, we also determined urinary BK levels, renal kallikrein (KLK) and angiotensin-converting enzyme (ACE) activity as well as renal cortical mRNA levels of neutral endopeptidase 24.11 (NEP) and low-molecular weight (LMW) kininogen. STZ led to a reduction of renal KLK and ACE activity and NEP expression and to a three-fold increase of urinary BK excretion and renal kininogen expression. Icatibant given alone had no effect on these parameters. In contrast, ramipril treatment normalized urinary protein and BK excretion as well as kininogen mRNA expression without affecting NEP mRNA expression or KLK and ACE activity. Our data demonstrate that renal BK is increased in severe STZ-induced diabetes mellitus, but may affect glomerular regulation only to a minor degree under this condition. However, kinins are partly involved in the antiproteinuric action of ACEI at this stage of diabetic nephropathy.
Tschöpe
Carsten
C
Department of Cardiology and Pneumology, University Hospital Benjamin Franklin, Free University of Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany. ctschoepe@yahoo.com
Seidl
Ulrich
U
Reinecke
Alexander
A
Riester
Udo
U
Graf
Kristof
K
Schultheiss
Heinz Peter
HP
Hilgenfeldt
Ulrich
U
Unger
Thomas
T
D000199:Actins / Q000096:biosynthesis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D065094:Bradykinin B2 Receptor Antagonists; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000473:pathology; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy*; D006977:Hypertension, Renal / Q000150:complications; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D016234:Kallikrein-Kinin System / Q000502:physiology; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology; D007677:Kidney Function Tests; D007704:Kininogens / Q000096:biosynthesis; D007705:Kinins / Q000502:physiology*; D008297:Male; D015260:Neprilysin / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011507:Proteinuria / Q000188:drug therapy* / Q000209:etiology; D017257:Ramipril / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D000199:Actins; D000806:Angiotensin-Converting Enzyme Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D065094:Bradykinin B2 Receptor Antagonists; D007004:Hypoglycemic Agents; D007328:Insulin; D007704:Kininogens; D007705:Kinins; C065679:icatibant; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D017257:Ramipril; D001920:Bradykinin