Effect of a serotonin blocking agent on renal hemodynamics in the normal rat

Effect of a serotonin blocking agent on renal hemodynamics in the normal rat. These studies were designed to explore the effects of ketanserin (K), a serotonergic S2-receptor blocker on glomerular filtration rate (GFR), renal plasma flow (RPF) and autoregulation of renal blood flow (RBF) in the normal, anesthetized rat. Two doses of ketanserin were used: a high dose that, in addition to its serotonin blocking effect, possessed alpha 1-adrenergic blocking capacities; and a low dose that acted only as a serotonin S2 blocking agent. The effects of the high dose were compared to the effects of phenotolamine. Both the high dose of K and phentolamine resulted in a similar fall of systemic blood pressure from 117 ± 4 to 78 ± 3 and from 121 ± 4.5 to 76 ± 5mm Hg, respectively (P < 0.01). Despite this fall, GFR and RPF remained unchanged from 2.36 ± 0.16 ± to 2.26 ± 0.12 ml/min, and from 5.33 ± 0.41 to 5.76 ± 0.5ml/min with K, while both parameters significantly decreased with phentolamine. A remarkable preservation of the autoregulation of RBF until a renal perfusion pressure (RPP) of 70 to 75mm Hg was noted with K, but not with phentolamine or Ringer infusion. With the low dose of K, a significant rise in GFR and PAH clearance was noted, from 2.12 ± 0.17 to 2.59 ± 0.18 and from 4.81 ± 0.35 to 5.66 ± 0.48 ml/min, respectively (P < 0.05). A similar preservation of autoregulation of RBF was observed. Our studies suggest that in the pressure ranges below normal autoregulation of RBF in the rat, serotonin blockade is associated with maintenance of both GFR and RBF

Effect of a serotonin blocking agent on renal hemodynamics in the normal rat

Effect of a serotonin blocking agent on renal hemodynamics in the normal rat. These studies were designed to explore the effects of ketanserin (K), a serotonergic S2-receptor blocker on glomerular filtration rate (GFR), renal plasma flow (RPF) and autoregulation of renal blood flow (RBF) in the normal, anesthetized rat. Two doses of ketanserin were used: a high dose that, in addition to its serotonin blocking effect, possessed alpha 1-adrenergic blocking capacities; and a low dose that acted only as a serotonin S2 blocking agent. The effects of the high dose were compared to the effects of phenotolamine. Both the high dose of K and phentolamine resulted in a similar fall of systemic blood pressure from 117 ± 4 to 78 ± 3 and from 121 ± 4.5 to 76 ± 5mm Hg, respectively (P < 0.01). Despite this fall, GFR and RPF remained unchanged from 2.36 ± 0.16 ± to 2.26 ± 0.12 ml/min, and from 5.33 ± 0.41 to 5.76 ± 0.5ml/min with K, while both parameters significantly decreased with phentolamine. A remarkable preservation of the autoregulation of RBF until a renal perfusion pressure (RPP) of 70 to 75mm Hg was noted with K, but not with phentolamine or Ringer infusion. With the low dose of K, a significant rise in GFR and PAH clearance was noted, from 2.12 ± 0.17 to 2.59 ± 0.18 and from 4.81 ± 0.35 to 5.66 ± 0.48 ml/min, respectively (P < 0.05). A similar preservation of autoregulation of RBF was observed. Our studies suggest that in the pressure ranges below normal autoregulation of RBF in the rat, serotonin blockade is associated with maintenance of both GFR and RBF

Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia

Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1—c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)—both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD