Angiotensinogen gene null-mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption

Angiotensinogen gene null-mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption. Chronic volume depletion by dietary salt restriction causes marked decrease in glomerular filtration rate (GFR) with little increase in urine osmolality in angiotensinogen gene null mutant (Agt−/−) mice. Moreover, urine osmolality is insensitive to both water and vasopressin challenge. In contrast, in normal wild-type (Agt+/+) mice, GFR remains remarkably constant and urine osmolality is adjusted promptly. Changes in volume status also cause striking divergence in renal structure between Agt−/− and Agt+/+ mice. Thus, in contrast to the remarkably stable glomerular size of Agt+/+ mice, glomeruli of Agt−/− mice are atrophied during a low salt and hypertrophied during a high salt diet. Moreover, the renal papilla, a structure unique to mammals and essential for urine diluting and concentrating mechanisms, is hypoplastic in Agt−/− mice. Thus, angiotensin is essential for the two fundamental homeostatic functions of the mammalian kidney, namely stable GFR and high urine diluting and concentrating capacity during alteration in extracellular fluid (ECF) volume. This is not only accompanied by angiotensin’s tonic effects on renal vasomotor tone and tubule transporters, but also accomplished through its capacity to affect the structure of both the glomerulus and the papilla directly or indirectly

Adipocytes do not significantly contribute to plasma angiotensinogen

Recently, it has been reported that 25% of plasma angiotensinogen (Agt) is derived from fat. Meanwhile, liver-specific Agt knockout (KO) mice have markedly low plasma Agt, which may be due to reduced fat mass. To study the contribution of the fat to plasma Agt, we tested whether increasing fat mass can elevate plasma Agt and blood pressure in liver- Agt KO mice. Epididymal fat mass in liver- Agt KO mice fed a high-fat diet (HFD) was 4.1-fold larger than that in liver- Agt KO mice on a normal-fat diet (NFD). The liver- Agt KO mice on NFD were hypotensive with low levels of plasma Agt (on average, 0.11 vs 2.38 μg/ml). HFD slightly increased plasma Agt (0.17 μg/ml) without increase in blood pressure. To further increase fat mass, liver- Agt KO mice were fed HFD and simultaneously supplemented with low-dose angiotensin II and compared with control mice. Fat mass was comparable between the two groups. However, liver- Agt KO mice had uniformly low plasma Agt (0.09 vs 2.07 μg/ml) and systolic blood pressure (78±12 vs 111±6 mm Hg). In conclusion, adipocyte-derived Agt has essentially no contribution to the plasma concentration and no impact on blood pressure compared to liver-derived Agt