We recently standardized a model (LLact) of severe chronic kidney disease based on impaired nephrogenesis by suppression of angiotensin II activity during lactation (Machado FG, Poppi EP, Fanelli C, Malheiros DM, Zatz R, Fujihara CK. Am J Physiol Renal Physiol 294: F1345–F1353, 2008). In this new study of the LLact model, we sought to gain further insight into renal injury mechanisms associated with this model and to verify whether the renoprotection obtained with the association of the angiotensin II receptor blocker losartan (L) and hydrochlorothiazide (H), which arrested renal injury in the remnant kidney model, would provide similar renoprotection. Twenty Munich-Wistar dams, each nursing six pups, were divided into control, untreated, and LLact groups, given losartan (L; 250 mg·kg−1·day−1) until weaning. The male LLact offspring remained untreated until 7 mo of age, when renal functional and structural parameters were studied in 17 of them, used as pretreatment control (LLactPre), and followed no further. The remaining rats were then divided among groups LLact+V, untreated; LLact+L, given L (50 mg·kg−1·day−1) now as a therapy; LLact+H, given H (6 mg·kg−1·day−1); and LLact+LH, given L and H. All parameters were reassessed 3 mo later in these groups and in age-matched controls. At this time, LLact rats exhibited hypertension, severe albuminuria, glomerular damage, marked interstitial expansion/inflammation, enhanced cell proliferation, myofibroblast infiltration, and creatinine retention. L monotherapy normalized albuminuria and prevented hypertension and the progression of renal injury, inflammation, and myofibroblast infiltration. In contrast to the remnant model, the LH combination promoted only slight additional renoprotection, perhaps because of a limited tendency to retain sodium in LLact rats.
ACE-I vs angiotensin II receptor antagonists: prevention of renal injury in chronic rat models