Paradoxical expressions of natriuretic peptide receptor-C and neutral endopeptidase account for C-type natriuretic peptide decline during the progression of experimental obstructive nephropathy

Abstract

Introduction: C-type natriuretic peptide (CNP) selectively binds to the guanylyl cyclase coupled natriuretic peptide receptor (NPR)-B and exerts more potent antihypertrophic and antifibrotic properties. Elimination of CNP occurs mainly by neutral endopeptidase (NEP) and NPR-C. Methods:We established a rat model of unilateral ureteral obstruction (UUO) to examine the continuous change of the CNP expression and to assess the correlations of NPR-B, NPR-C, NEP with CNP in the obstructed kidneys. Results: The expressions of CNP mRNA and protein in the obstructed kidneys tended to be higher immediately after ligation and declined at later time points compared to sham-operated rats, measured by real-time polymerase chain reaction (PCR) and western blot analysis. Subsequent correlation analysis indicated that CNP mRNA was positively correlated with p<0.05). In addition, the increased expression of NPR-C (r=−0.943 and −0.837 for mRNA and protein respectively, p<0.05) and NEP (r=−0.687 and −0.823 for mRNA and protein respectively, p<0.05) were accompanied by a significant decline in CNP. Conclusions: A high level of CNP may contribute to the elevated expression of NPR-B in the early phase of UUO. More interestingly, paradoxical expressions of NPR-C and NEP may account for the decline of CNP in the obstructed kidneys.

Receptor Signaling and Neutral Endopeptidase are Involved in the Resistance of C-Type Natriuretic Peptide to Human Mesangial Proliferation and Collagen-Iv Expression

“…Our recent in vivo study demonstrated that renal CNP expression tended to be higher within 24 hours after UUO and declined thereafter 6. The elevated expression of NPR-B may contribute to the overexpressed CNP in the early phase, whereas the sustained expression of NEP helps to, at least partly, account for the subsequent decline of CNP 34 35. However, the present study showed that NEP expression was significantly decreased after CNP treatment in MCs in vitro.…”

Exogenous C-type natriuretic peptide infusion ameliorates unilateral ureteral obstruction-induced tubulointerstitial fibrosis in rats

“…30 Our previous study demonstrated that renal expressions of CNP mRNA and protein tended to be higher in the acute stage of TIF, but progressively declined in the advanced stage. 11 In this context, we hypothesize that CNP supplementation may be a promising strategy for the treatment of TIF.…”

“…12 However, epithelial-mesenchymal transition, combined with the paradoxical expressions of NPR-C and neutral endopeptidase (NEP), may account for the decline of CNP in the advanced stages of nephropathies. 10,11 In contrast to regulation of blood pressure and body fluid homeostasis, the known physiological actions of CNP include local vasorelaxation, inhibition of organ remodeling, acceleration of reendothelialization, and antagonism of the reninangiotensin-aldosterone system. [13][14][15][16] Izumiya et al 17 examined the effects of exogenous CNP administration (0.05 mg/kg/min  2 weeks) on C57BL/6 mice with angiotensin II pretreatment, and found that angiotensin II-induced upregulation of collagen-I (Col-I), Col-III, and glyceraldehyde-3-phosphate dehydrogenase oxidase 4 in hearts was significantly suppressed by exogenous CNP infusion.…”