The aim of this study was to ascertain the quantitative importance of glucagon in mediating protein-induced increases in renal blood flow (RBF) and glomerular filtration rate (GFR) during the postprandial state. Six chronically instrumented conscious dogs were each subjected to four protocols: normal protein control meal (C); high protein meat meal (M); somatostatin infusion and meat (S + M); and glucagon infusion. C produced small increases in RBF (12 +/- 2%) and GFR (14 +/- 2%) without changing arterial plasma glucagon. M produced marked increases in RBF (38 +/- 4%), GFR (41 +/- 5%), and glucagon (from 23.3 +/- 3.6 to 73.3 +/- 7.1 pg/ml) over a 3-h period. During S + M, RBF and GFR failed to increase while glucagon was suppressed by 36 +/- 8% over a 2-h period. When S was stopped, glucagon rose to 100 +/- 13.9 pg/ml over the next hour, yet RBF and GFR increased by only 14 +/- 4 and 10 +/- 3%, respectively. Glucagon infusion (3 ng X kg-1 X min-1, i.v.) markedly elevated plasma glucagon to 131.6 +/- 27.3 pg/ml, yet neither RBF nor GFR significantly changed. These data indicate that while a protein-rich meat meal does elevate arterial plasma glucagon, the rise is not great enough to elicit significant changes in renal hemodynamics. Thus, elevated plasma levels of glucagon cannot account for protein-mediated increases in RBF and GFR during the postprandial state.

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This study was designed to examine the role of increased renal artery pressure (RAP) in mediating escape from the antidiuretic action of vasopressin (AVP). In six conscious dogs in which RAP was permitted to increase, AVP infusion, at a rate (0.2 mU X kg-1 X mm-1 iv) that was acutely subpressor, gradually raised mean arterial pressure (MAP) from 97 +/- 2 to 126 +/- 4 mmHg after 5 days while decreasing urine volume and increasing urine osmolality. However, after 4-5 days of AVP infusion, urine volume and osmolality returned to control, and the hypertensive effect of AVP waned so that after 9 days of AVP, MAP averaged only 113 +/- 5 mmHg. In contrast, when RAP was prevented from increasing in seven dogs with a servo-controlled aortic occluder, AVP caused sustained decreases in urine volume and elevated urine osmolality from 609 +/- 27 to 1,160-1,711 mosmol/kg H2O throughout 8 days of infusion. The hypertensive effect of AVP did not wane when RAP was servo-controlled, and after 8 days of AVP infusion, MAP averaged 152 +/- 7 mmHg, compared with a control of 96 +/- 2 mmHg. Servo-controlling RAP also prevented the marked sodium and chloride losses seen with chronic AVP infusion in normal dogs. These findings indicate that escape from the antidiuretic action of AVP is mediated by increased RAP, which causes diuresis and natriuresis, thereby diminishing the hypertensive effect of AVP. However, when pressure diuresis and natriuresis are prevented, AVP causes severe chronic hypertensive, suggesting that AVP could be an important hypertensive mechanism when renal function is impaired.

An increased incidence of renal tubular adenomas and carcinomas was identified in the 2-year CD-1 mouse carcinogenicity study with empagliflozin (sodium-glucose transporter 2 inhibitor) in high dose (1,000 mg/kg/day) male mice. A 13-week mouse renal investigative pathogenesis study was conducted with empagliflozin to evaluate dose dependency and temporal onset of nonneoplastic degenerative/regenerative renal tubular and molecular (genes, pathways) changes which precede neoplasia. Male and female CD-1 mice were given daily oral doses of 0, 100, 300, or 1,000 mg/kg/day (corresponding carcinogenicity study dose levels) for 1, 2, 4, 8, or 13 weeks. The maximum expected pharmacology with secondary osmotic diuresis was observed by week 1 at ≥100 mg/kg/day in both genders. Histopathologic kidney changes were first detected after 4 weeks of dosing in the male 1,000 mg/kg/day dose group, with progressive increases in the incidence and/or number of findings in this dose group so that they were more readily detected during weeks 8 and 13. Changes detected starting on week 4 consisted of minimal single-cell necrosis and minimal increases in mitotic figures. These changes persisted at an increased incidence at weeks 8 and 13 and were accompanied by minimal to mild tubular epithelial karyomegaly, minimal proximal convoluted tubular epithelial cell hyperplasia, and a corresponding increase in Ki-67-positive nuclei in epithelial cells of the proximal convoluted tubules. There were no corresponding changes in serum chemistry or urinalysis parameters indicative of any physiologically meaningful effect on renal function and thus these findings were not considered to be adverse. Similar changes were not identified in lower-dose groups in males nor were they present in females of any dose group. RNA-sequencing analysis revealed male mouse-specific changes in kidney over 13 weeks of dosing at 1,000 mg/kg/day. Treatment-related changes included genes and pathways related to p53-regulated cell cycle and proliferation, transforming growth factor β, oxidative stress, and renal injury and the number of genes with significant expression change dramatically increased at week 13. These treatment-related changes in genes and pathways were predominant in high-dose males and complemented the observed temporal renal tubular changes. Overall, these mouse investigative study results support the role of early empagliflozin-related degenerative/regenerative changes only observed in high-dose male CD-1 mice as a key contributing feature to a nongenotoxic mode of renal tumor pathogenesis.

We describe a servo-control system for acute and chronic regulation of renal perfusion pressure or pressures in other parts of the circulation. The system employs a Dacron-reinforced inflatable silastic occluder of sufficient strength and durability to produce large pressure gradients for long periods of time (at least 10 days) in the abdominal aortas of large dogs. The occluder is inflated with an inexpensive, bidirectional DC motor syringe pump that is controlled by a comparator feedback circuit connected to the output of a driver amplifier of a Grass polygraph or any other suitable recorder. The system has a rapid response time for precise control and has been used to maintain a constant renal perfusion pressure in experiments lasting as long as 10 days. The system has diverse applications in studies of acute or chronic regulation of renal hemodynamics as well as the hemodynamics of other organ systems. The main advantages of this system, besides its durability and precision of control, are that it is very inexpensive (total cost including the syringe pump is less than $150), easy to construct, and can be used in chronic studies for servo-controlling renal perfusion pressure or pressures in other parts of the circulation.