Alterations in glomerular dynamics in congenital, unilateral hydronephrosis.

We have previously shown that rats with congenital, unilateral hydronephrosis exhibit a reduction in GFR that returns to normal when either the renin angiotensin system or thromboxane A2 (TxA2) is blocked. The current study defines the single nephron defect in congenital, unilateral hydronephrosis and evaluates the roles of angiotensin II (Ang II) and TxA2 in this renal derangement. Renal micropuncture experiments were performed on the right kidney of rats from an inbred colony with unilateral right-sided hydronephrosis (HYDRO), or non-affected litter mates (CONTROL). In addition, four separate groups of hydronephrotic animals were treated with either the TxA2 receptor antagonist SQ-29548 (SQ), one of two Ang II receptor antagonists [saralasin (SAR) or DuP-753 (DUP)]; or combined treatment with DuP-753 and SQ-29,548 (S&D). SNGFR was significantly reduced (P < 0.05) in HYDRO compared to CONTROL (17.6 +/- 2.0 vs. 35.9 +/- 3.7 nl/min, respectively). Treatment with SQ-29,548 normalized SNGFR (29.0 +/- 3.0 nl/min), while saralasin and DuP-753 resulted in only a partial recovery of function (25.6 +/- 1.6 and 27.8 +/- 1.4 nl/min, respectively). Combined SQ-29,548 and DuP-753 treatment resulted in full recovery of SNGFR to 32.9 +/- 4.4 nl/min. The glomerular ultrafiltration coefficient (Kf) was reduced (P < 0.05) approximately 45% in HYDRO compared to CONTROL (1.64 +/- .08 vs. 2.84 +/- .22 nl/min/mm Hg, respectively). Kf returned to control levels in SAR, DUP and SQ, and increased above control in S&D (5.58 +/- 1.6 nl/min/mm Hg). There were no differences (P > 0.05) in hydrostatic or oncotic pressures across the glomerular capillary between any of the groups studied. The observation that Kf increases above CONTROL with combined blockade of TxA2 and Ang II suggests that these regulatory hormones decrease Kf via independent mechanisms. These data indicate that the reduction in SNGFR in congenital, unilateral hydronephrosis is a result of a marked fall in Kf that is mediated by both Ang II and TxA2.

Upregulation of renin-angiotensin system and downregulation of kallikrein in obstructive nephropathy.

The purpose of this study was to delineate the effects of prolonged (1 and 5 wk) unilateral ureteral obstruction (UUO) on the intrarenal renin-angiotensin and kallikrein-kinin systems in the rat. Systolic blood pressure (SBP) and plasma angiotensin (ANG) II levels were significantly higher at 1 and 5 wk of obstruction than in sham-operated groups. Also, plasma renin activity and ANG I levels were elevated at 1 wk (P < 0.05), and plasma angiotensin-converting enzyme (ACE)-kininase II activity was elevated at 5 wk (P < 0.05). Blockade of ANG II receptors with losartan (Dup 753) prevented the rise in SBP after UUO and normalized SBP in chronically hypertensive UUO rats. Renin mRNA levels and ANG II content were elevated in the obstructed kidneys at 1 and 5 wk compared with sham-operated kidneys (P < 0.05). ACE-kininase II activity was elevated in both the obstructed and contralateral kidneys at 5 wk compared with sham-operated kidneys (P < 0.05). In marked contrast to renin, total immunoreactive kallikrein contents and tissue kallikrein mRNA levels in the obstructed kidneys were reduced to 25% of sham-operated kidneys both at 1 and 5 wk (P < 0.001). The results indicate that urinary obstruction activates renin and suppresses kallikrein gene expression. Activation of ACE-kininase II by UUO also serves to enhance intrarenal ANG II generation and kinin degradation. The results implicate ANG II overproduction and kinin deficiency in the pathogenesis of UUO-induced hypertension and intrarenal vasoconstriction.