Pituitary adenylate cyclase-activating polypeptide prevents contrast-induced nephropathy in a novel mouse model

Abstract

We determined whether pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) prevents contrast-induced nephropathy using human renal proximal tubule epithelial (HK-2) cells and homozygous endothelial nitric oxide synthase-deficient (eNOS−/−) mice as a novel in vivo model. Cultured HK-2 cells were pretreated with 10−9–10−6 mol/L PACAP or vasoactive intestinal peptide (VIP) for 1 h, and then exposed to ionic (Urografin) or nonionic (iohexol) contrast media at 50 mg iodine/mL for 24 h. Male eNOS−/− mice received Urografin (1.85 g iodine/kg) intravenously after water deprivation for 24 h, and PACAP38 (10 μg) intraperitoneally 1 h before and 12 h after Urografin injection. Urografin and iohexol increased lactate dehydrogenase and kidney injury molecule 1 in the culture medium, induced apoptosis, and inhibited cell proliferation in HK-2 cell cultures. PACAP38 and VIP reduced these changes in a dose-dependent manner. PACAP38 was more potent than VIP. In eNOS−/− mice, Urografin raised serum creatinine and cystatin C levels, caused renal tubule damage, induced apoptosis, and promoted neutrophil influx. Urografin also increased kidney protein levels of proinflammatory cytokines, and kidney mRNA levels of proinflammatory cytokines, kidney injury biomarkers, and enzymes responsible for reactive oxygen and nitrogen species. PACAP38 significantly reduced these Urografin-induced changes in eNOS−/− mice. This study shows that both Urografin and iohexol are toxic to HK-2 cells, but Urografin is more toxic than iohexol. Urografin causes acute kidney injury in eNOS−/− mice. PACAP38 protects HK-2 cells and mouse kidneys from contrast media and is a potential therapeutic agent for contrast-induced nephropathy.

Nephroprotective activity of the enriched polyphenol extract of Euterpe edulis Martius

“…Pathological changes, such as vacuolar degeneration, intense vacuolization of proximal tubular cells and balloonization, were also described by Eduardo-Carraro et al (2016) and Yokomaku et al (2008), who studied rats with induced nephropathy. Therefore, in addition to the above-described biochemical parameters, our histopathological data indicate a significant disturbance of the renal structure in the NIC group in comparison with the control animals, which is in agreement with other studies (Billings et al 2008;Yokomaku et al, 2008;Khan et al, 2013).…”

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

“…Changes due to the addition of recombinant PACAP include increased cell survival, inhibition of upregulated apoptotic pathways and decreased production of pro-inflammatory and profibrotic substances [8]. Data from in vivo animal studies in rodents confirm a nephroprotective effect of PACAP in ischemia-caused renal damage [14,15,16,17,18], multiple myeloma [10,19], diabetic nephropathy [20], contrast induced nephropathy [21] and renal damage due to cisplatin [11,12] and cyclosporine A [13]. PACAP administration in those in vivo models leads to improvement of renal function, decreased tubulointerstitial damage and decreased expression of inflammatory and fibrotic markers [8].…”

Pituitary adenylate cyclase-activating polypeptide (PACAP) protects against mitoxantrone-induced cardiac injury in mice

“…The cytoprotective effects of PACAP have been most extensively studied in the brain and kidney [40, 69, 72]. PACAP has both direct and indirect cytoprotective effects in the brain and kidney [32, 72]. The direct protective effects of PACAP in the brain and kidney are mediated mainly via the cyclic AMP/protein kinase A signal transduction pathway, while the indirect protective effects of PACAP are mediated by multiple signal transduction pathways [32, 69, 72].…”

“…PACAP has both direct and indirect cytoprotective effects in the brain and kidney [32, 72]. The direct protective effects of PACAP in the brain and kidney are mediated mainly via the cyclic AMP/protein kinase A signal transduction pathway, while the indirect protective effects of PACAP are mediated by multiple signal transduction pathways [32, 69, 72]. PACAP protects the brain, kidney and liver against ischemia/reperfusion injury [28, 31, 59, 68] and protects the brain and kidney from injury caused by a wide range of therapeutic agents [2, 32, 40, 41, 69].…”

“…The direct protective effects of PACAP in the brain and kidney are mediated mainly via the cyclic AMP/protein kinase A signal transduction pathway, while the indirect protective effects of PACAP are mediated by multiple signal transduction pathways [32, 69, 72]. PACAP protects the brain, kidney and liver against ischemia/reperfusion injury [28, 31, 59, 68] and protects the brain and kidney from injury caused by a wide range of therapeutic agents [2, 32, 40, 41, 69]. Despite extensive library screens by major pharmaceutical companies over several decades, small molecule orthosteric agonists have not been found for the cognate receptors for any member of the secretin/growth hormone-releasing hormone/VIP family [24, 27].…”