Renal function and cortical blood flow during the recovery phase of acute renal failure

Renal function and cortical blood flow during the recovery phase of acute renal failure. The characteristics of the recovery process in dichromate-induced acute renal failure were determined. Rats were studied 1, 4, 7, and 14 days after the s.c. injection of either saline or potassium dichromate. In the sham-injected control animals, all values at each interval were similar. The typical pattern of acute renal failure was seen one day after dichromate injection: glomerular filtration rate (GFR) fell 80%, total renal blood flow (TRBF) was reduced 35%, the proportional flow to the outer cortex was diminished, and the urinary to plasma (U/P) inulin clearance was reduced. The early recovery phase, days 4 and 7, was characterized by: 1) a mild but significant diuresis, 2) progressive improvement in GFR and an increase in the proportional flow to the outer cortex, which actually exceeded control values, 3) a dissociation between improvement in renal function and changes in TRBF, since GFR increased progressively while TRBF remained relatively fixed, and 4) improvement in GFR that was associated with a progressive and parallel increase in absolute perfusion of the outer cortex. The present data suggest that the recovery process occurs in two stages. In the first stage, the restoration of outer cortical perfusion and renal function precedes the recovery of TRBF and tubular function, which occur during the second stage of the recovery process.Fonction rénale et débit sanguin rénal cortical au cours de la période de récupération de l'insuffisance rénale aiguë. Les caractéristiques du processus de récupération après une insuffisance rénale aiguë induite par le dichromate, ont été déterminées. Des rats ont été étudiés 1, 4, 7, et l4 jours après l'injection s.c. de dichromate de potassium ou de soluté salé. Chez les animaux contrôles, toutes les valeurs obtenues sont semblables. L'aspect typique de l'insuffisance rénale aiguë est observée un jour après l'injection de dichromate: GFR diminue de 80%, le débit sanquin rénal (TRBF) est réduit de 35%, la fraction de ce débit délivrée au cortex superficiel diminue et le U/P de l'inuline est abaissé. La phase de récupération précoce, aux jours 4 et 7, est caractérisée par: 1) une diurèse peu importante mais significativement plus grande, 2) une amélioration progressive de GFR et une augmentation de la fraction du débit délivrée au cortex superficiel, qui devient supérieure aux valeurs contrôles, 3) une dissociation entre l'amélioration de la fonction rénale indiquée par l'augmentation progressive de GFR, et TRBF qui reste relativement bas, 4) et une amélioration de GFR qui est associée à une augmentation progressive et parallèle du débit absolu de perfusion du cortex superficiel. Ces résultats suggèrent que le processus de récuparation survient en deux étapes. A la première étape, la récupération du débit cortical superficiel et de la fonction rénale précède la récupération de TRBF et de la fonction tubulaire qui constitue la deuxième étape

Effects of potassium depletion on renal tubular chloride transport in the rat

Effects of potassium depletion on renal tubular chloride transport in the rat. Potassium depletion (KD) causes renal chloride-wasting. To investigate the effects of KD on renal tubular reabsorption of chloride, balance, clearance, micropuncture, and microinjection studies were performed on potassium-depleted rats. KD was produced by omitting potassium from the diet and by administration of DOC A on days 2 and 3; rats were studied on days 9 to 12. Diets were chloride-free in both control and KD groups. In the KD group, balance experiments confirmed greater chloride depletion and continued chloride-wasting, and clearance studies showed an increased FECl. Muscle potassium was reduced by 27% as compared to control. Whole kidney and single nephron GFR were reduced in KD rats to 72 and 74% of control. Fractional (6 ± 6% vs. 22 ± 4%, P < 0.05) and absolute chloride reabsorption in the proximal tubule were reduced in KD, and chloride delivery out of the proximal tubule was not different. Fractional reabsorption of delivered chloride was reduced in the loop of Henle (92 ± 0.8% in KD vs. 95 ± 0.7% in control, P < 0.02). Transtubular chloride ratio (0.28 ± 0.02 vs. 0.21 ± 0.02, P < 0.02) was increased at the early distal tubule. Fractional delivery of chloride (8 ± 0.9 vs. 5 ± 0.5%, P < 0.02), and fluid (26 ± 1 vs. 22 ± 1%, P < 0.05) were also increased in KD at the early distal tubule. Recovery of chloride 36 injected into late distal tubules was 88 ± 1% on a normal chloride intake, 62 ± 2% in chloride depletion, and 88 ± 2% in potassium and chloride depletion. Thus, KD depresses chloride reabsorption in the proximal tubule and in the loop of Henle, and it decreases chloride 36 efflux from the collecting duct

Toll-like Receptor 7 and TLR9 Dictate Autoantibody Specificity and Have Opposing Inflammatory and Regulatory Roles in a Murine Model of Lupus

SummaryAntibodies (Abs) to RNA- and DNA-containing autoantigens are characteristic of systemic lupus erythematosus (SLE). We showed previously that Toll-like receptor (TLR) 9, recognizing DNA, is required for the spontaneous generation of DNA autoantibodies, but not for the development of lupus nephritis in susceptible mice. We report that lupus-prone mice deficient in TLR7, a receptor for ssRNA, failed to generate Abs to RNA-containing antigens (Ags) such as Smith (Sm) Ag. TLR9 and TLR7 also had dramatic effects on clinical disease in lupus-prone mice. In the absence of TLR9, autoimmune disease was exacerbated, lymphocytes and plasmacytoid DCs were more activated, and serum IgG and IFN-α were increased. In contrast, TLR7-deficient mice had ameliorated disease, decreased lymphocyte activation, and decreased serum IgG. These findings reveal opposing inflammatory and regulatory roles for TLR7 and TLR9, despite similar tissue expression and signaling pathways. These results have important implications for TLR-directed therapy of autoimmune disease

Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus

Systemic autoimmune disease in humans and mice is characterized by loss of immunologic tolerance to a restricted set of self-nuclear antigens. Autoantigens, such as double-stranded (ds) DNA and the RNA-containing Smith antigen (Sm), may be selectively targeted in systemic lupus erythematosus because of their ability to activate a putative common receptor. Toll-like receptor 9 (TLR9), a receptor for CpG DNA, has been implicated in the activation of autoreactive B cells in vitro, but its role in promoting autoantibody production and disease in vivo has not been determined. We show that in TLR9-deficient lupus-prone mice, the generation of anti-dsDNA and antichromatin autoantibodies is specifically inhibited. Other autoantibodies, such as anti-Sm, are maintained and even increased in TLR9-deficient mice. In contrast, ablation of TLR3, a receptor for dsRNA, did not inhibit the formation of autoantibodies to either RNA- or DNA-containing antigens. Surprisingly, we found that despite the lack of anti-dsDNA autoantibodies in TLR9-deficient mice, there was no effect on the development of clinical autoimmune disease or nephritis. These results demonstrate a specific requirement for TLR9 in autoantibody formation in vivo and indicate a critical role for innate immune activation in autoimmunity

Mutation of A DNA Repair Enzyme Causes Lupus in Mice

A replication study of a previous genome-wide association study (GWAS) suggested that a SNP linked to the POLβ gene is associated with systemic lupus erythematosus (SLE). This SNP is correlated with decreased expression of Pol β, a key enzyme in the base excision repair (BER) pathway. To determine whether decreased Pol β activity results in SLE, we constructed a mouse model of POLβ that encodes an enzyme with slow DNA polymerase activity. We show that mice expressing this hypomorphic POLβ allele develop an autoimmune pathology that strongly resembles SLE. Of note, the mutant mice have shorter immunoglobulin heavy-chain junctions and somatic hypermutation is dramatically increased. These results demonstrate that decreased Pol β activity during the generation of immune diversity leads to lupus-like disease in mice, and suggest that decreased expression of Pol β in humans is an underlying cause of SLE

The Ultrastructural Localization of Transport ATPase in the Rat Liver at Nonbile Canalicular Plasma Membranes

Na,K-ATPase in rat livers was localized cytochemically at the ultrastructural level. The Ernst technique, a method using p-nitrophenylphosphate (pNPP) substrate, was used to demonstrate ouabainsensitive, K-dependent phosphatase, an enzyme of the Na,K-ATPase reaction sequence. Reaction product was localized predominantly on the sinusoidal and non-bile canalicular (intercellular) surfaces. This localization contrasts with previous histochemical studies using ATP substrate and with models that have considered the transport enzyme to be localized at the canalicular surface. I f Na,K-ATPase is of importance in bile salt independent flow, a significant presence of the enzyme at sites other than the canalicular membrane suggests that a paracellular movement of sodium and water into the conaliculus must be considered. © 1979, American Gastroenterological Association. All rights reserved