Rationale: Cleavage of the extra-cellular domain of the (pro)renin receptor (PRR) yields a soluble fragment (sPRR). Although changes in plasma sPRR levels have been reported in hypertension, the causal role of sPRR in blood pressure (BP) regulation is unknown. Objective: Determine the role of sPRR in BP regulation at baseline and following Ang-II induced hypertension. Methods and Results: CRISPR-Cas9 was used to mutate the cleavage site of the PRR such that sPRR is not generated. Because the gene encoding PRR is on the X-chromosome and male mutant sPRR mice are infertile, only male mice were studied. Mutant sPRR mice had virtually undetectable plasma sPRR levels compared to littermate controls. Mutant sPRR mice had normal survival and development and no apparent histological abnormalities in the kidney, heart or aorta despite lower body weight. During normal Na+ intake, no differences in food or water intake, urinary water or Na+ excretion, or acid-base status were observed between control and mutant sPRR mice. Compared to controls, mutant sPRR mice had lower BP at baseline and an attenuated hypertensive response to 2 weeks of Ang-II infusion (400 ng/kg/min) which was partially reversed by infusion of mouse recombinant sPRR. Mutant sPRR mice also had lower albuminuria, renal tubular injury and oxidative stress relative to control mice post Ang-II infusion. Further, mesenteric arteries from mutant sPRR mice displayed reduced Ang-II-induced vasocontraction and greater acetylcholine, but not sodium nitroprusside, evoked vasorelaxation under baseline conditions. Conclusions: Loss of sPRR reduces BP at baseline and decreases Ang-II induced hypertension and renal injury. These effects of sPRR loss are associated with greater endothelium-dependent but not independent vasorelaxation of resistance-sized arteries.

Background We report follow-up data from an ongoing prospective cohort study of COVID-19 in pediatric kidney transplantation through the Improving Renal Outcomes Collaborative (IROC). Methods Patient-level data from the IROC registry were combined with testing, indication, and outcomes data collected to describe the epidemiology of COVID testing, treatment, and clinical outcomes; determine the incidence of a positive COVID-19 test; describe rates of COVID-19 testing; and assess for clinical predictors of a positive COVID-19 test. Results From September 2020 to February 2021, 21 centers that care for 2690 patients submitted data from 648 COVID-19 tests on 465 patients. Most patients required supportive care only and were treated as outpatients, 16% experienced inpatient care, and 5% experienced intensive care. Allograft complications were rare, with acute kidney injury most common (7%). There was 1 case of respiratory failure and 1 death attributed to COVID-19. Twelve centers that care for 1730 patients submitted complete testing data on 351 patients. The incidence of COVID-19 among patients at these centers was 4%, whereas the incidence among tested patients was 19%. Risk factors to predict a positive COVID-19 test included age > 12 years, symptoms consistent with COVID-19, and close contact with a confirmed case of COVID-19. Conclusions Despite the increase in testing and positive tests over this study period, the incidence of allograft loss or death related to COVID-19 remained extremely low, with allograft loss or death each occurring in < 1% of COVID-19-positive patients and in less than < 0.1% of all transplant patients within the IROC cohort. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information Supplementary Information The online version contains a graphical abstract available at 10.1007/s00467-022-05570-w.

Two recent clinical trials, using sodium glucose cotransporter (SGLT2) or endothelin-A receptor (ET-A) blocker, reported the first efficacious treatments in 18 years to slow progression of diabetic kidney disease. We hypothesized that combined inhibition of SGLT2 and endothelin-A receptor may confer greater protection against renal injury than either agent alone. Uninephrectomized male db/db mice were randomized to 4 groups - vehicle, SGLT2 inhibitor - dapagliflozin (dapa, 1 mg/kg/day), ET-A blocker - atrasentan (atra, 5mg/kg/day) or dual treatment from 10 weeks until 22 weeks of age. At 10 weeks of age, no differences were observed in body weight, blood glucose or urinary albumin excretion among the 4 groups. At 16 and 22 weeks of age, body weight was lower and blood glucose levels higher in the vehicle and atra groups compared to dapa and dual treated groups. No notable differences were observed among the 4 groups in urinary albumin excretion at week 16 and 22. Histological analysis showed mild glomerulosclerosis and tubular injury (<5%) in all 4 groups with reduced glomerulosclerosis in the dual treatment group compared to vehicle. Individual or combined treatment with an SGLT2 inhibitor and/or an ET-A antagonist did not confer renoprotective effects in this model.

Cleavage of the extra-cellular domain of the (pro)renin receptor (PRR) yields a soluble fragment (sPRR), which maybe involved in mediating hypertension. We recently developed a novel mouse model with mutation in the cleavage site of the PRR using CRISPR/Cas9 such that sPRR is not generated and showed that absence of sPRR attenuated angiotensin-II induced hypertension and kidney damage. In this study, we examined if sPRR alters blood pressure (BP) in angiotensin-II independent hypertension using deoxycorticosterone acetate (DOCA)-salt treatment. Mutant sPRR mice and littermate controls were treated with DOCA (50 mg/kg) and high Na + diet for 3 weeks. BP was monitored by radio-telemetry and metabolic balance studies performed at the end of the study (Day 17-18). Compared to controls, male mutant sPRR mice had markedly lower plasma sPRR levels (control: 21.5 ± 2.5 vs mutant 0.2 ± 0.03 ng/ml) and baseline BP (systolic control: 122 ± 3 vs mutant 114 ± 3; diastolic control: 94 ±5 vs mutant 82 ± 3 mm Hg). BP remained low in mutant sPRR mice relative to controls following 12 days of DOCA-salt treatment (systolic control: 141 ± 2 vs mutant 132 ± 5; diastolic control: 110 ± 4 vs mutant 95 ± 5 mm Hg). Mutant sPRR mice had lower body weight but similar food intake and urinary albumin excretion compared to controls (Table 1). Mutant sPRR mice had lower urine volume, water intake and urinary K + but not Na + excretion. No differences in renal histology were noted between control and mutant sPRR mice. Loss of sPRR attenuates DOCA-salt mediated hypertension. The mechanisms by which sPRR might regulate BP and water/Na + homeostasis in DOCA-salt hypertension are currently being investigated.