Development of diabetic nephropathy in the Milan normotensive strain, but not in the Milan hypertensive strain: possible permissive role of hemodynamics.
BACKGROUND
Rats of the Milan normotensive strain develop spontaneous glomerulosclerosis, whereas those of the Milan hypertensive strain are resistant to renal disease, possibly due to intrarenal artery hypertrophy protecting from systemic hypertension. To assess the role of hemodynamic versus metabolic factors in diabetic nephropathy, we investigated whether streptozotocin-induced diabetes accelerates glomerulosclerosis in Milan normotensive and/or removes (the hemodynamic) protection in Milan hypertensive rats by reducing preglomerular vascular resistance.


METHODS
Diabetic and nondiabetic Milan normotensive, hypertensive, and progenitor Wistar rats were followed for 6 months for the assessment of renal function and structure.


RESULTS
Proteinuria increased in nondiabetic and diabetic normotensive and, to a lesser extent, in diabetic Wistar, but not hypertensive rats. Serum creatinine increased and creatinine clearance decreased in nondiabetic and diabetic normotensive rats at 6 months. At 1.5 months, diabetic normotensive, but not hypertensive rats showed increased glomerular filtration rate and filtration fraction, suggesting glomerular hypertension. Diabetic nephropathy was detected in diabetic normotensive and Wistar, but not hypertensive rats. Glomerular extracellular matrix and TGF-beta mRNA levels increased with diabetes (and age) in normotensive, but not hypertensive rats. Arterioles and interlobular arteries showed increased media thickness in hypertensive versus normotensive rats, with diabetes reducing it only in the normotensive.


CONCLUSIONS
These data show that Milan hypertensive rats are not susceptible to diabetic nephropathy, at variance with glomerulosclerosis-prone Milan normotensive rats, thus indicating the importance of genetic background. Our study suggests that the nature of this (genetic) protection might be hemodynamic, with intrarenal artery hypertrophy preventing diabetes-induced loss of autoregulation.
Pugliese
Giuseppe
G
Department of Clinical Sciences and Department of Experimental Medicine and Pathology, "La Sapienza" University, Rome, Italy. giuseppe.pugliese@uniroma1.it
Pricci
Flavia
F
Barsotti
Paola
P
Iacobini
Carla
C
Ricci
Carlo
C
Oddi
Giovanna
G
Romeo
Giulio
G
Leto
Gaetano
G
Marano
Giuseppe
G
Sorcini
Mariella
M
Sabbatini
Massimo
M
Fuiano
Giorgio
G
Di Mario
Umberto
U
Pugliese
Francesco
F
D000818:Animals; D001794:Blood Pressure; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology*; D005109:Extracellular Matrix / Q000235:genetics; D006439:Hemodynamics; D006973:Hypertension / Q000235:genetics*; D007668:Kidney / Q000473:pathology; D011507:Proteinuria; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics
D017931:DNA Primers; D016212:Transforming Growth Factor beta