Chronic administration of furosemide augments renal weight and glomerular capillary pressure in normal rats

Abstract

Angiotensin II (ANG II) is believed to promote progressive renal injury via augmented glomerular capillary hydraulic pressure (PGC). Acute volume reduction secondary to diuretic administration increases circulating ANG II and augments PGC, yet the hemodynamic effects of sustained diuretic administration are unknown. Therefore, glomerular micropuncture studies were performed in male Munich-Wistar rats after 6–8 wk of treatment with daily furosemide (F, 40 mg/day), furosemide plus the AT1 receptor antagonist, losartan (F + L, 5 mg/day), or no therapy (C, control). Renal weight was increased in F rats (1.23 ± 0.7 g) vs. C (1.00 ± 0.06 g) or F + L (0.97 ± 0.01 g). In addition, PGC was elevated in F animals (52.1 ± 1.5 mmHg) vs. C (43.7 ± 1.5) or F + L-treated rats (41.3 ± 1.7). F-treated rats were also characterized by a relative increase in efferent arteriolar resistance and filtration fraction. The latter was markedly attenuated in F + L-treated animals. Collectively, these findings are consistent with an ANG II-mediated alteration in intrarenal hemodynamics. In contrast to acute volume manipulations, however, chronic furosemide augmented renal growth, whereas losartan administration completely arrested this phenomenon. Further studies are warranted to determine whether the hemodynamic and growth adaptations elicited by chronic F administration induce or accelerate renal injury.

Permissive role of nitric oxide in macula densa control of renin secretion

“…While some studies suggest an acute and probably direct relaxing effect of loop diuretics on venous tone, mean arterial blood pressure does not appear to be systematically altered in the short term before major salt losses have occurred (1,21,33,37). Furthermore, if the renal baroreceptor is located in the JGA region of the afferent arteriole, the renal vasodilatation typically seen with loop diuretics may cause an increase, not a decrease in pressure at the site of the baroreceptor, because it is well established that these agents cause an increase in glomerular capillary pressure (5,23,27). In addition, our studies in the isolated kidney show that the increase in perfusion flow rate caused by bumetanide is only between 5 and 10%, a change that is unlikely to be primarily responsible for the marked increase in renin release.…”

Proximal and Distal Nephron-specific Adaptation to Furosemide

“…Pappa2, an IGF-1 binding protein protease, known to increase IGF-1 bioavailability is up-regulated in TAL cells. Also, furosemide treatment increases the kidney-to-body weight ratio of rats 22,23,72 and now, mice, and the proximal tubule comprises the bulk of nephron mass (by immunofluorescence and flow cytometry, data not shown). Thus, we postulated that a furosemide-induced increase in proximal tubule cell size would be necessary and sufficient to increase kidney size.…”

“…Pappa2, an IGF-1 binding protein protease, known to increase IGF-1 bioavailability is up-regulated in TAL cells. Also, furosemide treatment increases the kidney-to-body weight ratio of rats 22,23,72 and now, mice, and the proximal tubule Egfr and Pten knockout mice, Harris and colleagues showed that tonic PI3-kinase signaling can override anti-proliferative genes in unstimulated kidneys 84 . In their model, unilateral nephrectomy further increased contralateral kidney size implying that additional pathways can generate a hypertrophic response.…”

“…For example, with inhibition of NCC, NCC-expressing cells in the distal convoluted tubule (DCT) show apoptosis 19 whereas increased activation of NCC increases the mass of DCT 20,21 . Furosemide treatment increases the kidney-to-body weight ratio in rodent studies 22,23 . The mechanisms of cell plasticity are unknown and hypertrophy of only a short segment such as the DCT is unlikely to account for increases in weight of the total kidney.…”

An association of losartan-hydrochlorothiazide, but not losartan-furosemide, completely arrests progressive injury in the remnant kidney

“…Glomerular hypertrophy has been pointed out as one of the initiating factors leading to the development of glomerulosclerosis (23,29), along with an elevation of P GC (5,17,18,31), presumably because these two abnormalities synergistically increase mechanical stretching of the glomerular wall (13), thus leading to glomerular cell proliferation and to the production of inflammatory mediators (21). The action of furosemide on P GC in the Nx model has not been examined, but it is noteworthy that P GC has been previously shown to be elevated in normal rats treated with furosemide for 6 -8 wk (33), raising the possibility that persistence of both tuft enlargement and intracapillary hypertension limited any renoprotective effect that the natriuretic action of furosemide might have provided. The mechanisms underlying these effects are unclear.…”