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The Impact of the Nitric Oxide (NO)/Soluble Guanylyl Cyclase (Sgc) Signaling Cascade on Kidney Health and Disease: a Preclinical Perspective

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The Impact of the Nitric Oxide (NO)/Soluble Guanylyl Cyclase (Sgc) Signaling Cascade on Kidney Health and Disease: a Preclinical Perspective International Journal of Molecular Sciences Review The Impact of the Nitric Oxide (NO)/Soluble Guanylyl Cyclase (sGC) Signaling Cascade on Kidney Health and Disease: A Preclinical Perspective Shalini M. Krishnan 1, Jan R. Kraehling 1, Frank Eitner 1,2, Agnès Bénardeau 1 ID and Peter Sandner 1,3,* 1 Bayer AG, Cardiovascular Research, Pharma Research Center, 42096 Wuppertal, Germany; [email protected] (S.M.K.); [email protected] (J.R.K.); [email protected] (F.E.); [email protected] (A.B.) 2 Division of Nephrology and Clinical Immunology, RWTH Aachen University, 52062 Aachen, Germany 3 Department of Pharmacology, Hannover Medical School, 30625 Hannover, Germany * Correspondence: [email protected] Received: 15 May 2018; Accepted: 8 June 2018; Published: 9 June 2018 Abstract: Chronic Kidney Disease (CKD) is a highly prevalent disease with a substantial medical need for new and more efficacious treatments. The Nitric Oxide (NO), soluble guanylyl cyclase (sGC), cyclic guanosine monophosphate (cGMP) signaling cascade regulates various kidney functions. cGMP directly influences renal blood flow, renin secretion, glomerular function, and tubular exchange processes. Downregulation of NO/sGC/cGMP signaling results in severe kidney pathologies such as CKD. Therefore, treatment strategies aiming to maintain or increase cGMP might have beneficial effects for the treatment of progressive kidney diseases. Within this article, we review the NO/sGC/cGMP signaling cascade and its major pharmacological intervention sites. We specifically focus on the currently known effects of cGMP on kidney function parameters. Finally, we summarize the preclinical evidence for kidney protective effects of NO-donors, PDE inhibitors, sGC stimulators, and sGC activators. Keywords: nitric oxide; cGMP; chronic kidney disease; soluble guanylyl cyclase; sGC; sGC stimulator; sGC activator 1. Summary The number of patients with chronic kidney diseases has dramatically increased in recent years, driven by the constant increase in life expectancy and the steadily increasing prevalence of risk factors such as diabetes, obesity or hypertension. Besides the progressively declining kidney function harboring a poor prognosis for patients, enormous economic costs—especially for hemodialysis and kidney transplantation—cause a huge and constantly growing burden for healthcare systems. Therefore, intense research and clinical development efforts are ongoing to identify signaling pathways which are critical for maintenance of kidney function and to investigate new pharmacological interventions for the treatment of kidney diseases. In recent years, it has become obvious that, along with the natriuretic peptide (NP)/particulate guanylyl cyclase (pGC)/cyclic guanosine monophosphate (cGMP) signaling cascade, the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP pathway plays a pivotal role for the regulation of physiological kidney function. The disruption of the NO/sGC/cGMP pathways results in the decrease of cGMP levels and can cause severe kidney pathologies. Within this review article, we summarize the current understanding how NO/sGC/cGMP systems regulate physiological kidney function by targeting renal blood vessels and vascular smooth muscle cells, but also by having an impact on renal innervation, glomeruli, mesangial cells, podocytes, macula densa and tubular cells. In addition, we discuss how impairment of this pathway in different functional kidney Int. J. Mol. Sci. 2018, 19, 1712; doi:10.3390/ijms19061712 www.mdpi.com/journal/ijms Int. J. Mol.Int. J. Sci. Mol.2018 Sci. ,201819,, 1712 19, x 2 of 182 of 18 mesangial cells, podocytes, macula densa and tubular cells. In addition, we discuss how impairment compartmentsof this pathway leads toin chronicdifferent kidney functional pathologies. kidney compartments Finally, we summarizeleads to chronic the current kidney pharmacologicalpathologies. approaches,Finally, aimingwe summarize to restore the NO/cGMPcurrent pharmacological signaling for approaches, the treatment aiming of kidney to restore diseases. NO/cGMP Here, we signaling for the treatment of kidney diseases. Here, we focus on cGMP increase via NO donors, focus on cGMP increase via NO donors, inhibition of cGMP degradation by PDE-inhibitors and direct inhibition of cGMP degradation by PDE-inhibitors and direct stimulation of the soluble guanylyl stimulation of the soluble guanylyl cyclase (sGC) by sGC stimulators and sGC activators. cyclase (sGC) by sGC stimulators and sGC activators. 2. The NO/sGC/cGMP Signaling 2. The NO/sGC/cGMP Signaling In 1998,In 1998, Drs. Drs. Robert Robert Furchgott, Furchgott, Louis Louis Ignarro, Ignarro, and Ferid Ferid Murad Murad were were awarded awarded the theNobel Nobel Prize Prize in Physiologyin Physiology and and Medicine Medicine “for “for their their discoveries discoveries concerning NO NO as asa signaling a signaling molecule molecule in the in the cardiovascularcardiovascular system”. system”. These These researchers researchers unveiled unveiled the molecular molecular nature nature of ofthe the “Endothelial “Endothelial Derived Derived RelaxingRelaxing Factor Factor (EDRF)” (EDRF)” to be to the be gasthe NO,gas NO, which which is produced is produced by theby the endothelium endothelium and and potently potently dilates blooddilates vessels. blood Further vessels. research Further demonstrated research demonstrated that NO isthat of NO broad is of importance broad importance not only not for only the for regulation the of vascularregulation tone of via vascular smooth tone muscle via smooth cell relaxation, muscle cell but relaxation, this signaling but this system signaling is also system active is also in a active variety of in a variety of other cells types. Depending on the site of action, it influences nerve function and other cells types. Depending on the site of action, it influences nerve function and synaptic transmission, synaptic transmission, has antifibrotic and antiproliferative effects, influences blood clotting and has antifibrotic and antiproliferative effects, influences blood clotting and inflammatory processes inflammatory processes and is present in adipocytes with impact on fat metabolism. The signaling and iscascade—especially present in adipocytes for withthe vasodilatory impact onfat effects—is metabolism. very The well signaling understood cascade—especially and schematically for the vasodilatorysummarized effects—is in Figure very 1. well understood and schematically summarized in Figure1. FigureFigure 1. The 1. The NO/sGC NO/sGC and and NP/pGC signaling signaling cascade cascade with withmajor majorpharmacological pharmacological intervention intervention sites. NO/sGC- and NP/pGC-derived cGMP predominantly targets cGMP-dependent protein kinases sites. NO/sGC- and NP/pGC-derived cGMP predominantly targets cGMP-dependent protein kinases (PKG/cGK), but also has mediates its actions though cyclic nucleotide-gated (CNG) ion channels and (PKG/cGK), but also has mediates its actions though cyclic nucleotide-gated (CNG) ion channels the activation or inhibition of phosphodiesterases (PDEs). The differential expression of enzyme and theisoforms activation in various or inhibition cells and of tissues, phosphodiesterases which mediate (PDEs).cellular effects, The differential also have a expression direct impact of enzymeon isoformskidney in function. various The cells signaling and tissues, cascade which is currently mediate targeted cellular on the effects, level of alsocGMP have production a direct (nitrates, impact on kidneysGC function. stimulators, The and signaling sGC activators) cascade isand currently cGMP degradation targeted on (PDE5 the leveland ofPDE9 cGMP inhibitors). production (nitrates,Abbreviations: sGC stimulators, ANP: Atrial and sGCnatriuretic activators) peptide; and cGMPBNP: Brain degradation natriuretic (PDE5 peptide; and PDE9cGK: cGMP- inhibitors). Abbreviations:dependent ANP:protein Atrial kinases; natriuretic cGMP: cyclic peptide; guanosine BNP: Brainmonophosphate; natriuretic CNG: peptide; Cyclic cGK: nucleotide-gated cGMP-dependent proteinion kinases; channels; cGMP: CNP: C-type cyclic guanosinenatriuretic peptide; monophosphate; GTP: cyclicCNG: guanosine Cyclic triphosphate; nucleotide-gated GMP: guanosine ion channels; CNP:monophosphate; C-type natriuretic NO: peptide; Nitric GTP:oxide; cyclic NOS: guanosine Nitric oxide triphosphate; synthase; NP: GMP: Natriuretic guanosine peptide; monophosphate; PDE: NO: NitricPhosphodiesterase; oxide; NOS: pGC: Nitric particulate oxide synthase; guanylyl NP: cyclase; Natriuretic PKG: Protein peptide; kinase PDE: G; sGC: Phosphodiesterase; Soluble guanylyl pGC: cyclase. particulate guanylyl cyclase; PKG: Protein kinase G; sGC: Soluble guanylyl cyclase. The signaling starts with the formation of NO as a by-product during the conversion of L-arginine Theto L -citrulline, signaling a starts reaction with catalyzed the formation in the presence of NO as ofa the by-product nitric oxide during synthase the (NOS) conversion enzyme. of ThereL-arginine to L-citrulline,are three adifferent reaction catalyzedNOS isoforms in the identified presence ofin themammals: nitric oxide neuronal synthase (nNOS/NOS1), (NOS) enzyme. inducible There are three(iNOS/NOS2), different NOS and isoforms endothelial identified (eNOS/NOS3). in mammals: eNOS-derived neuronal NO (nNOS/NOS1), stimulates soluble inducible guanylyl (iNOS/NOS2), cyclase and endothelial (eNOS/NOS3). eNOS-derived NO stimulates soluble guanylyl cyclase (sGC)—an
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