Genetic renal disease classification by hormonal axes
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REVIEW
Genetic renal disease classification by hormonal axes Bar Rotem-Grunbaum 1 & Daniel Landau 1 Received: 11 August 2019 / Revised: 23 November 2019 / Accepted: 26 November 2019 # IPNA 2019
Abstract The kidneys, which regulate many homeostatic pathways, are also a major endocrinological target organ. Many genetic renal diseases can be classified according to the affected protein along such endocrinological pathways. In this review, we examine the hypothesis that a more severe phenotype is expected as the affected protein is located more distally along such pathways. Thus, the location of a defect along its endocrinological pathway should be taken into consideration, in addition to the mutation type, when assessing genetic renal disease severity. Keywords Kidney . Loss of function . Gain of function . Axis . Endocrine . Hormonal . Genetic
Introduction Endocrinological pathways are composed of a hormone synthesized in a remote tissue which then reaches a target organ, binds to a membrane or cytoplasmic receptor and activates a series of signal transduction molecules, culminating in the secretion of another hormone or a certain target organ function. The kidneys, which regulate many homeostatic pathways, are also a major endocrinological target organ (in addition to the control of other remote organs, such as bone marrow red blood cell production by erythropoietin). Many genetic renal diseases can be classified according to the affected protein along such endocrinological pathways. In this manuscript, we examine the hypothesis that the more distal the disease’s location on the specific axis, the more severe the disease phenotype. The different axes were divided by their point of origin in the remote organ. The pathways summarized in this review will include: 1. The renin-angiotensin/aldosterone system. Renin, secreted mostly by the macula densa, responds to different stimuli, including the sympathetic nervous system. Renin cleaves angiotensinogen to begin a cascade that culminates in the creation of Angiotensin II (Ang-II) by * Daniel Landau [email protected] 1
Department of Pediatrics B, Schneider Children’s Medical Center of Israel, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
angiotensin-converting enzyme (mostly by endothelium). Ang-II binds to the renal AT1 receptor. Ang-II has numerous effects on the kidney, including vasoconstriction (which affects, among others, also glomerular hemodynamics) as well as sodium reabsorption and fibrosis. 2. The aldosterone/ENaC pathway. Angiontensin II’s effects on the adrenal zona glomerulosa activate the synthesis and secretion of aldosterone. This is the beginning point for another axis where the kidney functions as a target organ: the aldosterone-mineralocorticoid receptor (MR)epithelial sodium channel (ENaC) axis. 3. Posterior hypophysis origin ADH axis, which leads to the activation of the renal ADH receptor and intracellular AQP2 channel activation, leading to water reabsorption. 4. Bone-derived fibroblast growth factor (FGF)-23 axis whic
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