The molecular basis of increased glomerulosclerosis after blockade of the renin angiotensin system in growth hormone transgenic mice.
BACKGROUND
Angiotensin converting enzyme inhibitor (ACEi) therapy delays the onset of renal failure in diabetic nephropathy and inhibits or delays the onset of proteinuria in several animal models.


METHODS
We examined this question using a transgenic model of chronic glomerulosclerosis caused by an excess production of growth hormone (GH) in which there is progressive glomerular scarring leading to uremia. In addition, since GH mice do not have systemic hypertension or an elevated glomerular filtration rate, we could address the question of whether ACEi or angiotensin II receptor antagonists (AII RA) had an effect on the development of glomerulosclerosis under these conditions. Since excess matrix accumulates in glomerulosclerosis because of alterations in the balance between its synthesis and degradation, we examined the effect of ACEi and AII RA on these parameters.


RESULTS
Systemic blood pressure was unaffected by ACEi treatment, but the glomerular filtration rate decreased 85%. ACEi-treated mice had increased mesangial deposition of type I collagen and decreased 105 kD complex collagenase activity. In addition, ACEi-treated GH mice had increased glomerular alpha 1 type I collagen, alpha 1 type IV collagen, and alpha-smooth muscle cell actin mRNAs. No changes were noted in beta actin, or 72 kD metalloproteinase mRNAs. The result of these changes was a net increase in sclerosis. Surprisingly, GH mice treated with ACEi or AngII RA developed marked renal arteriolar lesions.


CONCLUSIONS
In some forms of glomerulosclerosis, the lesions develop independently of angiotensin II. Pharmacological inhibition of angiotensin II, in this circumstance, may aggravate the lesions through disregulation of the levels and the balance between glomerular matrix synthesis and degradation.
Peten
E P
EP
Renal Cell Biology Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.
Striker
L J
LJ
Fogo
A
A
Ichikawa
I
I
Patel
A
A
Striker
G E
GE
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D017364:Collagenases / Q000187:drug effects / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D018093:Gelatinases / Q000187:drug effects / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000235:genetics; D013006:Growth Hormone / Q000235:genetics*; D007093:Imidazoles / Q000494:pharmacology; D007606:Juxtaglomerular Apparatus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D007678:Kidney Glomerulus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008233:Lymphotoxin-alpha / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000187:drug effects / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D012083:Renin / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D000199:Actins; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D008233:Lymphotoxin-alpha; D012333:RNA, Messenger; D013777:Tetrazoles; C070967:L 158809; D013006:Growth Hormone; D003094:Collagen; D002216:Captopril; D003404:Creatinine; D012083:Renin; D017364:Collagenases; D018093:Gelatinases; D013936:Thymidine