The prorenin receptor in the cardiovascular system and beyond.

Since the prorenin receptor (PRR) was first reported, its physiological role in many cellular processes has been under intense scrutiny. The PRR is currently recognized as a multifunctional receptor with major roles as an accessory protein of the vacuolar-type H+-ATPase and as an intermediary in the Wnt signaling pathway. As a member of the renin-angiotensin system (RAS), the PRR has demonstrated to be of relevance in cardiovascular diseases (CVD) because it can activate prorenin and enhance the enzymatic activity of renin, thus promoting angiotensin II formation. Indeed, there is an association between PRR gene polymorphisms and CVD. Independent of angiotensin II, the activation of the PRR further stimulates intracellular signals linked to fibrosis. Studies using tissues and cells from a variety of organs and systems have supported its roles in multiple functions, although some remain controversial. In the brain, the PRR appears to be involved in the central regulation of blood pressure via activation of RAS- and non-RAS-dependent mechanisms. In the heart, the PRR promotes atrial structural and electrical remodeling. Nonetheless, animals overexpressing the PRR do not exhibit cardiac injury. In the kidney, the PRR is involved in the development of ureteric bud branching, urine concentration, and regulation of blood pressure. There is great interest in the PRR contributions to T cell homeostasis and to the development of visceral and brown fat. In this mini-review, we discuss the evidence for the pathophysiological roles of the PRR with emphasis in CVD.

Hormone-Dependent Regulation of Renin and Effects on Prorenin Receptor Signaling in the Collecting Duct.

The production of renin by the principal cells of the collecting duct has widened our understanding of the regulation of intrarenal angiotensin II (Ang II) generation and blood pressure. In the collecting duct, Ang II increases the synthesis and secretion of renin by mechanisms involving the activation of Ang II type 1 receptor (AT1R) via stimulation of the PKCα, Ca2+, and cAMP/PKA/CREB pathways. Additionally, paracrine mediators, including vasopressin (AVP), prostaglandins, bradykinin (BK), and atrial natriuretic peptide (ANP), regulate renin in principal cells. During Ang II-dependent hypertension, despite plasma renin activity suppression, renin and prorenin receptor (RPR) are upregulated in the collecting duct and promote de novo formation of intratubular Ang II. Furthermore, activation of PRR by its natural agonists, prorenin and renin, may contribute to the stimulation of profibrotic factors independent of Ang II. Thus, the interactions of RAS components with paracrine hormones within the collecting duct enable tubular compartmentalization of the RAS to orchestrate complex mechanisms that increase intrarenal Ang II, Na+ reabsorption, and blood pressure.

The obesity paradox and orthopedic surgery.

ABSTRACT: The Obesity Paradox describes the counterintuitive finding that although obesity contributes to the development of chronic conditions such as chronic kidney disease and cardiovascular disease, obesity seems to improve mortality in patients with these diseases. This paradox has also been sited in the critical care literature in regard to acute kidney injury, obesity and mortality. This study's objective is to examine the impact of obesity and post-surgical acute kidney injury on hospital length of stay and 2-year mortality after orthopedic surgery.We reviewed the electronic medical records of all adult elective orthopedic surgery patients over 2 years in a large academic hospital. The 1783 patients who met inclusion criteria were divided into obese (body mass index, BMI ≥ 30, n = 1123) and non-obese groups (BMI <30, n = 660). Demographics, medications, comorbidities, and perioperative variables were included in multivariable logistic regression analyses with acute kidney injury, length of hospital stay, and two-year mortality as primary outcomes. Outcomes were analyzed for the entire group, the obese cohort and the non-obese cohort.Acute kidney injury developed in 5% of the post-surgical orthopedic patients. Obesity increased the likelihood of developing acute kidney injury post orthopedic surgery (odds ratio [OR] = 1.82; 95% Confidence interval [CI] 1.05-3.15, P = .034). Acute kidney injury increased length of stay by 1.3 days and increased the odds of two-year mortality (OR = 2.08; 95% CI 1.03-4.22, P = .041). However, obese patients had a decreased likelihood of two-year mortality (OR = 0.53; 95% CI 0.33-0.84, P = .009).In adult orthopedic surgery patients, obesity increased the risk of acute kidney injury. Patients who developed an acute kidney injury had longer hospital stays and higher two-year mortality. Paradoxically, obesity decreased two-year mortality.

Obesity, Angiotensin-Blocking Drugs, and Acute Kidney Injury in Orthopedic Surgery.

Postoperative acute kidney injury occurs in 7% to 11% of orthopedic surgeries. The effect of preoperative angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on the development of postoperative acute kidney injury remains controversial. Adipose tissue has its own independently regulated angiotensin system. The primary aim of this study was to examine the effects of obesity and preoperative ACEIs and ARBs on postoperative acute kidney injury. Charts were reviewed of adult elective orthopedic surgery patients during a 2-year period when patients were instructed to take their ACEI or ARB on the morning of surgery. The patients were divided into an obese cohort (body mass index [BMI] ≥30 kg/m2) and a nonobese cohort (BMI <30 kg/m2). A multivariable model was created for the outcome of acute kidney injury, using obesity as a primary predictor and adjusting for demographics, medications, comorbidities, and intraoperative parameters in a logistic regression analysis. Obesity increased the likelihood of developing acute kidney injury after orthopedic surgery (odds ratio [OR], 1.86; 95% CI, 1.07-3.22; P=.028). For every 5-unit increase in BMI, the odds of acute kidney injury were 1.43 (95% CI, 1.26-1.62; P<.001). When receiving ACEIs or ARBs, only the nonobese patients had a statistically increased likelihood of postoperative acute kidney injury (OR, 3.30; 95% CI, 1.12-9.70; P=.030). Obesity is an independent risk factor for postoperative acute kidney injury. Obesity appears to influence the effect that preoperative ACEIs and ARBs have on postoperative acute kidney injury. [Orthopedics. 2021;44(2):e253-e258.].

Upregulation of Cortical Renin and Downregulation of Medullary (Pro)Renin Receptor in Unilateral Ureteral Obstruction.

Chronic kidney disease (CKD) is characterized by renal dysfunction, which is a common feature of other major diseases, such as hypertension and diabetes. Unilateral ureteral obstruction (UUO) has been used as a model of CKD in experimental animals and consists of total obstruction of one kidney ureter. The UUO decreases renal blood flow, which promotes the synthesis of renin in the juxtaglomerular apparatus, the first step in renin-angiotensin system (RAS) cascade. RAS induces inflammation and remodeling, along with reduced renal function. However, it remains unknown whether intrarenal RAS (iRAS) is activated in early stages of CKD. Our objective was to characterize different iRAS components in the renal cortex and in the medulla in an early phase of UUO. Male C57BL/6 mice (8-12 weeks old) were subjected to UUO in the left kidney, or to sham surgery, and were euthanized after 7 days (n = 5/group). Renal function, renal inflammatory/remodeling processes, and iRAS expression were evaluated. UUO increased plasma creatinine, right renal hypertrophy (9.08 ± 0.31, P < 0.05 vs. Sham), and tubular dilatation in the left kidney cortex (42.42 ± 8.19µm, P < 0.05 vs. Sham). This correlated with the increased mRNA of IL-1ß (1.73 ± 0.14, P < 0.01 vs. Sham, a pro-inflammatory cytokine) and TGF-ß1 (1.76 ± 0.10, P < 0.001 vs. Sham, a pro-fibrotic marker). In the renal cortex of the left kidney, UUO increased the mRNA and protein levels of renin (in 35% and 28%, respectively, P < 0.05 vs. Sham). UUO decreased mRNA and protein levels for the (pro)renin receptor in the renal medulla (0.67 ± 0.036 and 0.88 ± 0.028, respectively, P < 0.05 vs. Sham). Our results suggest that modulation of iRAS components depends on renal localization and occurs in parallel with remodeling and pro-inflammatory/pro-fibrotic mechanisms.