Distribution and Function of PACAP and Its Receptors in the Healthy and Nephrotic Kidney

Abstract

Background/Aims: Plasma deficiency of pituitary adenylate cyclase-activating polypeptide (PACAP) was recently demonstrated in children with nephrotic syndrome (NS). Previous studies have reported an important protective effect of PACAP on kidney proximal tubules. The aim of this study was to explore the expression of PACAP and its receptors PAC1, VPAC1 and VPAC2 in the healthy and nephrotic kidney and to determine if PACAP has an effect on renal proximal tubular cells exposed to albumin. Methods: Expression of PACAP and its receptors was studied using kidney tissue from healthy and nephrotic children, and in 3 human renal cell lines (glomerular microvascular endothelial cells, podocytes and proximal tubular epithelial HK-2 cells). The functionality of the VPAC1 receptor was tested in HK-2 cells, measuring cyclic adenosine monophosphate levels after PACAP exposure. The influence of PACAP on cell viability and transforming growth factor-β1 (TGF-β1) expression was measured in HK-2 cells exposed to albumin, mimicking proteinuria related damage. Results: VPAC1 expression was detected in the tubular proximal epithelial cells and in the glomerular podocytes of renal tissue from healthy and nephrotic children. Increased staining for PACAP was found in the proximal tubules of renal sections from children with NS compared to healthy renal sections. Expression and functionality of VPAC1 were demonstrated in HK-2 cells. Finally, PACAP did not alter cell viability or TGF-β1 expression of HK-2 cells exposed to albumin. Conclusion: VPAC1 is the predominant receptor in the human kidney. The enhanced presence of PACAP in proximal tubular epithelial cells in nephrotic kidneys points to the reabsorption of filtered PACAP. On short term, PACAP has no in vitro effect on cell viability and TGF-β1 expression of proximal tubular epithelial cells exposed to high concentrations of albumin.

Physical Activity Protects the Pathological Alterations of Alzheimer’s Disease Kidneys via the Activation of PACAP and BMP Signaling Pathways

“…The protein expressions of all PACAP receptors recovered in TAD animals. VPAC1 has already been shown to be expressed in the highest level in proximal tubules (Eneman et al, 2016), and the expression of the PAC1 receptor was demonstrated in the HK-2 cell line (Li et al, 2010). Direct binding of PACAP in kidney diseases has been proven both on PAC1 and VPAC1 receptors (Li M. et al, 2008), suggesting their equal importance in AD-related disorders.…”

β-Arrestin-independent endosomal cAMP signaling by a polypeptide hormone GPCR

“…VIPR1 is natively expressed in the kidney 36 , and previous studies have documented endogenous VIPR1 expression in HEK293 cells 31 , 37 , 38 . We first sought to independently verify that endogenous VIPR1 is indeed responsible for the VIP-elicited cAMP elevation measured in our cell model.…”

The Neuropeptide Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Is Protective in Inflammation and Oxidative Stress-Induced Damage in the Kidney

“…There are very few studies addressing the presence and functional role of PACAP in the human kidney. A recent study by Eneman et al [92] found VPAC receptors in normal and nephrotic kidneys and described increased PACAP immunoreactivity in the proximal tubules of nephrotic children, pointing to the reabsorption of filtered PACAP. Another study found decreased PACAP immunoreactivity in tissue samples from renal cancer patients [93].…”