Search

Background: Chemokines orchestrate immune cells activation and infiltration during acute kidney injury (AKI)., Objectives: We aim to test whether deletion of C-C chemokine ligand 7 (CCL7), a small chemokine related to CCL2 (MCP-1), may modulate AKI development and progression toward kidney fibrosis., Method: Expression of CCL7 was quantified in murine cortical tubular (MCT) cells exposed to myoglobin or lipopolysaccharide or submitted to metabolic reprogramming. Kidney function (BUN, glomerular filtration rate), expression of CCL7 receptors, and kidney infiltration by inflammatory cells (F4/80+ macrophages, MPO+ neutrophils, and B220+ B-cells) were assessed in wt and Ccl7-/- mice submitted to 3 different models of AKI or kidney fibrosis (uni/bilateral ischemia/reperfusion injury (u/bIRI) and rhabdomyolysis)., Results: Toxin exposure of MCT cells, as well as metabolic reprogramming recapitulating AKI changes, led to a dramatic up-regulation of CCL7. In vivo, kidney expression of Ccl7 and Ccl2 significantly increased after AKI and remained increased beyond the acute phase (30 days after uIRI). The expression of the CCL7 receptors was heterogeneous and varied with time. Kidney function, expression of CCL7 receptors and Ccl2, and the number of inflammatory cells within kidneys were similar in wt and Ccl7-/- mice at baseline and at day 2 after AKI. Thirty days after uIRI, kidney fibrosis was similar in both mouse strains., Conclusions: Despite strong induction of CCL7 after AKI, CCL7 deficiency does not prevent AKI and the transition toward kidney fibrosis and should probably not be further explored as a potential target to prevent or treat AKI., (© 2024 S. Karger AG, Basel.)

Background: Alterations of renal hemodynamics play an essential role in renal homeostasis and kidney diseases. Recent data indicated that semaphorin 3C (SEMA3C), a secreted glycoprotein involved in vessel development, can modulate renal vascular permeability in acute kidney injury, but whether and how it might impact systemic and renal hemodynamics is unknown., Objectives: The objective of the study was to explore the effect of SEMA3C on systemic and renal hemodynamics., Methods: SEMA3C recombinant protein was administered intravenously in two-month-old wild-type mice, and the variations of mean arterial pressure, heart rate, renal blood flow, and renal vascular resistance were measured and analyzed., Results: Acute administration of SEMA3C induced (i) systemic hemodynamic changes, including mean arterial pressure decrease and heart rate augmentation; (ii) renal hemodynamic changes, including reduced vascular resistance and elevated renal blood flow. Continuous perfusion of SEMA3C had no significant effect on systemic or renal hemodynamics., Conclusion: SEMA3C is a potent vasodilator affecting both systemic and renal hemodynamics in mice., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Syndecan-1 (Sdc-1) and glypican-1 (Gpc-1) are 2 important proteoglycans found in the glycocalyx and believed to govern transvascular distribution of fluid and protein. In this translational study, we assessed Sdc-1 and Gpc-1 knockout (KO) on whole body water balance after an intravenous volume challenge. Sdc-1 and Gpc-1 KO mice had higher starting blood water content versus strain-matched controls. Sdc-1 KO mice exhibited a significantly higher diuretic response (87%; p < 0.05), higher excreted volume/infusion volume ratio (p < 0.01), higher extravascular/infused ratio, and greater tissue water concentration (60 vs. 52%). Collectively, these suggest differences in kidney response and greater fluid efflux from peripheral vessels. The CD1 strain and Gpc-1 KO had a 2-3-fold larger urine output relative to C57 strain, but Gpc-1 KO reduced the excreted/infused ratio relative to controls (p < 0.01) and they maintained plasma dilution longer. Thus, genetic KO of Sdc-1 and Gpc-1 resulted in markedly different phenotypes. This work establishes the feasibility of performing fluid balance studies in mice., (© 2020 S. Karger AG, Basel.)

Despite reports suggesting that tissue-resident natural killer (trNK) cells cause ischemic kidney injury, their contribution to the development of tubulointerstitial fibrosis has not been determined. This study hypothesized that the depletion of trNK cells may ameliorate renal fibrosis by affecting transglutaminase 2/syndecan-4 interactions. Aristolochic acid nephropathy (AAN) was induced in C57BL/6 mice as an experimental model of kidney fibrosis. The mice were treated with anti-asialo GM1 (ASGM1) or anti-NK1.1 antibodies to deplete NK cells. Although both ASGM1 and NK1.1 antibodies suppressed renal NKp46 ＋ DX5 ＋ NK cells, renal NKp46 ＋ DX5 - cells were resistant to suppression by ASGM1 or NK1.1 antibodies during the development of tubulointerstitial fibrosis in the AAN-induced mouse model. Western blot analysis showed that both antibodies increased the expression of fibronectin, transglutaminase 2, and syndecan-4. These findings indicate that trNK cells played an exacerbating role in tubulointerstitial fibrosis by activating transglutaminase 2 and syndecan-4 in the AAN-induced mouse model. [BMB Reports 2019; 52(9): 554-559].

Purpose: Human multidrug and toxin extrusion member 1 (MATE1, SLC47A1) and Organic Cation Transporter 2 (OCT2, SLC22A2) play important roles in the renal elimination of various pharmacologic agents, including the anti-diabetic drug metformin. The goal of this study was to determine the association between metformin's pharmacokinetics and pharmacodynamics and the genetic variants of MATE1 (rs2289669) and OCT2 (rs316019) before and after treatment with the potential MATE inhibitor, ranitidine., Methods: We recruited 26 healthy Koreans balanced across the OCT2 and MATE1 genetic variants, and conducted a prospective clinical trial to investigate their effects on metformin's pharmacokinetics and pharmacodynamics before and after ranitidine treatment., Results: Neither MATE1 rs2289669 nor OCT2 rs316019 affected metformin's pharmacokinetics and pharmacodynamics before ranitidine treatment. However, the renal clearance of metformin was significantly higher (15.2%) after ranitidine treatment in the MATE1 GG group compared with the MATE1 GA + AA group. Only the effect of MATE1 on the renal clearance of metformin after ranitidine treatment was significant (b = -0.465, p ≤ 0.05) after including demographic data and the OCT2 genotype in the model., Conclusion: Our study suggests that MATE1 rs2289669 may be a significant determinant in the renal clearance of metformin in the case of transporter-mediated drug interactions.

Occasionally, an original research paper has an unusually significant impact on a particular research field. Such a paper, published recently in Nature Genetics, describes the uncovering of the functional role of the Rh protein family--the proteins that express the Rh blood group antigens. Marini et al. (1) demonstrate how two human Rh glycoproteins can correct ammonium transport deficiency in mutant yeast cells. Rh proteins are therefore ammonium transporters--a role that, in vertebrates, has remained previously uncharacterized. These data herald a new era in Rh protein research, beyond their role as blood group antigens, and into the characterization of ammonium transport mechanisms, notably in the kidney.