Intrarenal Bradykinin (BK) is Decreased in Mice with Prorenin Receptor (PRR) Deficiency in the Collecting Duct

Abstract

The renin‐angiotensin system (RAS) and kallikrein‐kinin system (KKS) play a role in multiple physiological and pathological conditions, including the regulation of blood pressure (BP) and sodium reabsorption. The prorenin receptor (PRR), a key component of the RAS, is involved in the control of epithelial sodium channel (ENaC) and BP. Recently, our group reported that bradykinin (BK)/bradykinin type 2 receptor (B2R) activation stimulates the synthesis and release of prorenin/renin in collecting duct (M‐1) cells via PKC and nitric oxide (NO) pathways. We further demonstrated that mice with deficiency of PRR in the collecting ducts (CDPRR‐KO) exhibited attenuated BP and ENaC activity due to decreased amount of renin and angiotensin (Ang) II in the distal nephron during chronic Ang II‐induced hypertension. Taking together these data suggest that PRR is necessary for the activation of prorenin in the distal nephron segments. However, whether intrarenal BK contributes to the decreased levels of distal tubular prorenin/renin in CDPRR‐KO mouse model is unknown. To test the hypothesis that decreased intrarenal BK leads to diminished levels of renin in the collecting duct of CDPRR‐KO mice, we used two groups of mice (N=5–7), including: 1)CDPRR‐KO and Wild type (WT). Systolic blood pressure (SBP) measured by telemetry was decreased in KO compared with WT mice (112±2 vs.123±3 mmHg; P<0.05). The metabolic parameters: body weight, food intake, and water consumption did not show differences between CDPRR‐KO and WT mice. Urine amount of renin was decreased in KO mice (11.5±3 vs. 30.5±11 pg/mL; P<0.05). Plasma levels of BK were quantified by ELISA and resulted similar between both groups of mice (54±4 vs. 51±2 ng/mL; P=0.54). In contrast, urine levels of BK, measured as reflection of intrarenal BK, were significantly decreased in KO mice compared with WT (2.6±0.4 vs. 6.5±0.7 ng/mL; P<0.001). It is known that angiotensin converting enzyme (ACE) is responsible for BK degradation within the kidney. To further examine whether intrarenal ACE explain the differences in intrarenal BK, we quantified ACE activity using a fluoregenic peptide (Abz‐FRK(Dnp)P) in the presence or absence of ACE inhibition with Lisinopril. ACE activity did not differ between CDPRR‐KO and WT mice (5.1±0.2 vs. 4.2±0.5 AU/min/mg prot; P=0.340). In conclusion, these data indicate that intrarenal BK is decreased in CDPRR‐KO mice. Decreased levels of intrarenal BK explain, at least in part, the decreased levels of distal tubular prorenin/renin and ENaC activity in CDPRR‐KO mouse model. The mechanism by which BK is decreased in the kidney of CDPRR‐KO mice is not clear, but it could be a compensatory response in this model. Efforts will be done toward defining the role of PRR in the interactions between the RAS and the KKS and its actual contribution to the regulation of blood pressure.Support or Funding InformationNIDDK (DK‐104375) and LSU Health Sciences Center/Summer Research ProgramThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.