In vivo studies were conducted in Na-replete anesthetized male Wistar rats with denervated kidneys. Intrarenal injections of angiotensin-(1-7) [ANG-(1-7) at > 1 nmol/kg produced a shallow dose-dependent decrease in renal blood flow that was mediated by the AT1-type ANG II receptor. A constant intrarenal infusion of ANG-(1-7) at 0.1 and 1 nmol.min-1.kg-1 had minimal effects on renal blood flow and blood pressure and resulted in an elevated urinary excretion of Na and water compared with the time-control saline-infused group. To determine whether ANG-(1-7) may have a direct action on tubular epithelium to inhibit Na reabsorption, we examined the effect of ANG-(1-7) on transport-dependent O2 consumption (Qo2) in fresh suspensions of rat proximal tubules in vitro. ANG-(1-7) inhibited Qo2 in a concentration-dependent fashion with a threshold concentration of approximately 100 pM. Stimulating Na-K-adenosinetriphosphatase (Na-K-ATPase) activity with nystatin caused a leftward shift of the inhibitory concentration-response curve to ANG-(1-7). The 22% inhibition of Qo2 by 1 pM ANG-(1-7) was abolished by pretreatment with 5 mM ouabain (Na-K-ATPase inhibitor), unaltered by pretreatment with 1 microM PD-123319 (AT2 receptor antagonist), partially attenuated by 1 microM losartan (AT1 receptor antagonist), and abolished by 1 microM [Sar1, Thr8]ANG II (nonselective ANG receptor antagonist). Together these findings indicate that ANG-(1-7) has biological activity in the kidney and, at nonvasoconstrictor doses, results in increased Na and water excretion in vivo. One site of action is the proximal tubule, where ANG-(1-7) can inhibit an ouabain-sensitive Na-K-ATPase exit step in cellular Na transport. This novel inhibitory action of ANG-(1-7) appears to be mediated by an AT1 receptor (minor component) and a non-AT1, non-AT2 ANG receptor (major component).
Angiotensin IV, {[des-Asp1,Arg2]ANG II or ANG-(3—8)}, has been shown to preferentially bind to a novel angiotensin binding site (AT4receptor). The cellular location and function of this receptor in the rat kidney is unknown. Autoradiography localized AT4 receptors to the cell body and apical membrane of convoluted and straight proximal tubules in the cortex and outer stripe of the outer medulla. ANG IV (0.1 pM-1 μM) elicited a concentration-dependent decrease in transcellular Na+ transport (as measured by proximal tubule O2 consumption rates) in fresh suspensions of control or nystatin-stimulated (bypasses rate-limiting step of apical Na+entry) rat proximal tubules. The inhibitory effect of 1 pM ANG IV was unaltered by either 1 μM losartan (AT1-receptor antagonist) or 1 μM PD-123319 (AT2-receptor antagonist) and yet was abolished by 1 μM divalinal-ANG IV (AT4-receptor antagonist) or ouabain pretreatment. These results demonstrate that the kidney AT4-receptor system is localized to the proximal tubule and suggests that one potential biological role of this system is in the regulation of Na+ transport by inhibiting a ouabain-sensitive component of Na+-K+-adenosinetriphosphatase activity in the rat.
Lithotripsy shock waves (SW) to one renal pole damage that pole but protect the opposite pole from the damage inflicted by another, immediate application of SW. This study investigated whether the protection (1) occurs when the first treatment causes no injury, (2) is caused by SW or injury, (3) exhibits a threshold, and (4) occurs when the same pole receives both treatments. Six-to 7-wk-old anesthetized female pigs were studied. The following groups were studied: group 1 (n ؍ 4), 2000 SW at 12 kV to one pole and 2000 SW at 24 kV (standard) to the opposite pole; group 2 (n ؍ 6), same as group 1 except 500 12-kV SW pretreatment; group 3 (n ؍ 8), 500 12-kV, 2000 standard SW, all to the same pole; and group 4 (n ؍ 8), same as group 3 except 100 12-kV SW pretreatment. Mean ؎ SD lesion size in group 1, first pole treated, was 0.66 ؎ 0.82% of functional renal volume (FRV; P < 0.05 versus 5.22 ؎ 3.6% FRV with no pretreatment [NP]; 95% confidence interval [CI] ؊7.0 to ؊2.1) and 0.50 ؎ 0.68% FRV in the opposite pole after 2000 standard SW (P < 0.05 versus NP; 95% CI ؊9.4 to ؊0.08). Mean lesion size (first pole) in group 2 was 0.020 ؎ 0.028% FRV (P < 0.01 versus NP; 95% CI ؊9.2 to ؊1.2) and 0.43 ؎ 0.54% FRV in the opposite pole after 2000 standard SW (P < 0.05 versus NP; 95% CI ؊8.8 to ؊0.82). Same-pole SW (groups 3 and 4) also protected. Mean lesion sizes were 0.28 ؎ 0.33% (P < 0.01 versus NP; 95% CI ؊8.0 to ؊1.9) in group 3 and 0.39 ؎ 0.48% FRV (P < 0.01 versus NP; 95% CI ؊8.2 to ؊1.7) in group 4. It is concluded that the pretreatment protocol substantially limits the renal injury that normally is caused by SWL and occurs when the pretreatment and standard SW are applied to the same pole. The threshold for the protection may be <100 SW.
Both animal and human studies show that PCN is associated with an acute decline in renal function.
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