The physiological significance of the renal tubular prorenin receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na(+) excretion and investigated the signaling mechanisms by which PRR regulates Na(+) balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na(+) diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na(+) balance with normal- and low-Na(+) intake. PRR KO mice had an attenuated hypertensive response and reduced Na(+) retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na(+) channel (ENaC-α) expression. Treatment with mouse prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na(+) wasting and reduces the hypertensive response to ANG II.

The collecting duct is the predominant nephron site of prorenin and prorenin receptor (PRR) expression. We previously demonstrated that the collecting duct PRR regulates epithelial Na channel (ENaC) activity and water transport; however, which cell type is involved remains unclear. Herein, we examined the effects of principal cell (PC) or intercalated cell (IC) PRR deletion on renal Na and water handling. PC or IC PRR knockout (KO) mice were obtained by crossing floxed PRR mice with mice harboring Cre recombinase under the control of the AQP2 or B1 subunit of the H ATPase promoters, respectively. PC KO mice had reduced renal medullary ENaC-α abundance and increased urinary Na losses on a low-Na diet compared with controls. Conversely, IC KO mice had no apparent differences in Na balance or ENaC abundance compared with controls. Acute treatment with prorenin increased ENaC channel number and open probability in acutely isolated cortical collecting ducts from control and IC PRR KO, but not PC PRR KO, mice. Furthermore, compared with controls, PC KO, but not IC KO mice, had increased urine volume, reduced urine osmolality, and reduced abundance of renal medullary AQP2. Taken together, these findings indicate that PC, but not IC, PRR modulates ENaC activity, urinary Na excretion, and water transport.

Collecting duct (CD)-derived renin is involved in the hypertensive response to chronic angiotensin-II (Ang-II) administration. However, whether CD renin is involved in Ang-II independent hypertension is currently unknown. To begin to examine this, 12 week old male and female CD-specific renin knock out (KO) mice and their littermate controls were subjected to uni-nephrectomy followed by 2 weeks of deoxycorticosterone acetate (DOCA) infusion combined with a high salt diet. Radiotelemetric blood pressure (BP) was similar between KO and control mice at baseline; BP increased in both groups to a similar degree throughout the 2 weeks of DOCA-salt treatment. Urinary albumin excretion and plasma blood urea nitrogen were comparable between the two groups after DOCA-salt treatment. Fibrosis as assessed by Masson’s Trichrome stain/Sirius Red stain and collagen-1 mRNA expression was similar between control and KO mice. Compared to baseline, DOCA-salt treatment decreased plasma renin concentration (PRC), urinary renin excretion and medullary renin mRNA expression in both floxed and CD renin KO mice with no detectable differences between the two groups. Further, in primary culture of rat inner medullary CD, aldosterone treatment did not change renin activity or total renin content. Taken together, these data suggest that CD derived renin does not play a role in DOCA-salt hypertension.

Background We examined in persons with type 2 diabetes (T2D) whether the use of insulin and the risk of serious hypoglycemic events with insulin is higher in persons with more advanced CKD. Methods In a national cohort of 855,133 veterans with T2D seen at Veteran Affairs clinics between Jan 1, 2008 and December 31, 2010 with at least two serum creatinine measurements, we defined insulin use from pharmacy records and serious hypoglycemic events by ICD-9/10 codes from emergency room visits or hospitalizations that occurred until December 31, 2016. Results Mean age was 66 ± 11 years and 97% were men. Mean baseline eGFR was 73 ± 22 ml/min/1.73 m2. In a multivariable Cox regression model of those without insulin use at baseline (N = 653,200), compared to eGFR ≥90 group, eGFR < 30 group had higher hazard (HR 1.80, 95% CI 1.74 to 1.88) of subsequent insulin use. In a multivariable Cox model with propensity score matching for baseline insulin use (N = 305,570), both insulin use (HR 2.34, 95% CI 2.24 to 2.44) and advanced CKD (HR 2.28, 95% CI 2.07 to 2.51 for comparison of eGFR < 30 to eGFR ≥90 ml/min/1.73 m2 groups) were associated with increased risk of subsequent serious hypoglycemic events. Conclusions and relevance In T2D, more advanced CKD was associated with greater insulin use. Both insulin use and advanced CKD were risk factors for serious hypoglycemic events. The safety of insulin compared to newer glycemic agents in more advanced CKD needs further study.

Background: Guidelines recommend lowering systolic blood pressure below 130 mm Hg, irrespective of previous strokes. However, there is a concern that lowering systolic blood pressure in people with low baseline diastolic blood pressure might increase the risk of stroke. Methods: We conducted a secondary analysis of the Secondary Prevention of Small Subcortical Strokes trial that randomly assigned participants with a history of subcortical strokes to an intensive (<130 mm Hg; N=1519) or standard (130–149 mm Hg; N=1501) systolic targets. We examined the effects of blood pressure intervention on stroke and cardiovascular composite across the range of baseline diastolic blood pressure in spline regression models and tested for interaction of baseline diastolic blood pressure with the intervention on outcomes. Results: Mean baseline systolic and diastolic blood pressures were 143±19 and 78±11 mm Hg, respectively. Within each baseline diastolic blood pressure tertile, the achieved diastolic was lower in the intensive versus standard arm. There were 275 stroke events over 10 889 years of follow-up. Lower baseline diastolic blood pressure was associated with increased risk of stroke in an observational spline regression model. Hazard ratios relating blood pressure intervention with the risk of stroke in the lowest (hazard ratio, 0.78 [95% CI, 0.52–1.16]) and the highest (hazard ratio, 0.80 [95% CI, 0.53–1.21]) baseline diastolic tertiles were similar ( P =0.95). Results were similar for the cardiovascular composite. Conclusions: Intensive systolic control does not appear to increase the risk of stroke in those with low baseline diastolic blood pressure and prior stroke. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00059306.