Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci.

Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes.

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.

Genome-wide association study of kidney function decline in individuals of European descent.

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR.

Molecular origin of Na(+)/Li(+) exchanger: Evidence against the involvement of major cloned erythrocyte transporters.

Numerous studies have demonstrated heightened Na(+)/Li(+) countertransport (NLCT) activity in erythrocytes of patients with essential hypertension or diabetic nephropathy. The same carrier also contributes to the therapeutic action of lithium salt, widely used in the treatment of psychiatric disorders. However, the molecular origin of NLCT remains unknown.

NKCC1 and hypertension: a novel therapeutic target involved in the regulation of vascular tone and renal function.

Purpose Of Review: The present review summarizes recent advances in our understanding of the mechanisms involving the housekeeping Na+, K+, 2Cl(-) cotransporter (NKCC1) in blood pressure (BP) regulation.

Recent Findings: High-ceiling diuretics (HCDs), known potent inhibitors of NKCC1, renal-specific NKCC2 and four isoforms of K+, Cl(-) cotransporters decrease [Cl(-)]i, hyperpolarize vascular smooth muscle cells and suppress myogenic tone and contractions evoked by modest depolarization, phenylephrine, angiotensin II and uridine triphosphate. These actions are absent in NKCC1(-/-) mice, indicating that HCDs interact with NKCC1 rather than with other potential targets.

Hyperhomocysteinemia is not sufficient to cause preeclampsia in an animal model: the importance of folate intake.

Objective: The objective of our study was to determine whether methylenetetrahydrofolate reductase (Mthfr)-deficient mice develop preeclampsia (PE).

Study Design: Mice were placed on a normal or low-folate/high-methionine (LF/HM) diet to assess the impact of mild and severe homocysteinemia. Blood pressure and proteinuria were measured throughout gestation in Mthfr-deficient and control mice on both diets, by radiotelemetry and by determining the urinary albumin/creatinine ratio by enzyme-linked immunosorbent assay, respectively.

Altered phosphorylation of RRXS*/T* motif in ouabain-treated renal epithelial cells is not mediated by inversion of the [Na](i)/[K+](i) ratio.

Recently, we reported that the death of ouabain-treated C7-MDCK cells resembling principal cells from collecting ducts of the Madin-Darby canine kidney (MDCK) is caused by ouabain interaction with Na+,K+-ATPase but is not mediated by inversion of the [Na+](i)/[K+](i) ratio. The mechanism of this intriguing phenomenon remains unknown. We therefore examined the action of ouabain on serine/threonine phosphoproteins as possible intermediates of cell death signaling.

The death of ouabain-treated renal epithelial cells: evidence against anoikis occurrence.

The mechanisms of cell death signaling triggered by cardiotonic steroids are poorly understood. Based on massive detachment of ouabain-treated Madin-Darby canine kidney (MDCK) cells, it may be proposed that the cytotoxic action of these compounds is mediated by anoikis, i.e.

Purinergic inhibition of Na⁺,K⁺,Cl⁻ cotransport in C11-MDCK cells: Role of stress-activated protein kinases.

Previously, we observed that sustained activation of P2Y₁ leads to inhibition of Na⁺,K⁺,Cl⁻ cotransport (NKCC) in C11 cells resembling intercalated cells from collecting ducts of the Madin-Darby canine kidney. This study examined the role of stress-activated protein kinases (SAPK) in NKCC inhibition triggered by purinergic receptors. Treatment of C11 cells with ATP led to sustained phosphorylation of SAPK such as JNK and p38.

Vascular smooth muscle contraction evoked by cell volume modulation: role of the cytoskeleton network.

Previously, we reported that hyposmotic swelling evoked transient vascular smooth muscle cell (SMC) contraction that was completely abolished by L-type Ca(2+) channel blockers. In contrast, sustained contraction revealed in hyper- and isoosmotically-shrunken SMCs was insensitive to L-type channel blockers and was diminished in Ca(2+)-free medium by only 30-50%. Several research groups reported cell volume-dependent cytoskeleton network rearrangements.

[Na]i -induced c-Fos expression is not mediated by activation of the 5' -promoter containing known transcriptional elements.

In vascular smooth muscle cells and several other cell types, inhibition of Na(+)/K(+)-ATPase leads to the expression of early response genes, including c-Fos. We designed this study to examine whether or not a putative Na(+) (i)/K(+) (i)-sensitive element is located within the c-Fos 5'-UTR from - 650 to + 103 containing all known response elements activated by 'classic' stimuli, such as growth factors and Ca(2+) (i)-raising compounds. In HeLa cells, the highest increment of c-Fos mRNA content was noted after 6 h of Na(+)/K(+)-ATPase inhibition with ouabain that was abolished by actinomycin D, an inhibitor of RNA synthesis.

Insulin-like growth factor type-1 receptor transactivation in vasoactive peptide and oxidant-induced signaling pathways in vascular smooth muscle cells.

Transactivation of epidermal growth factor receptor (EGFR) is a well-documented mechanism by which vasoactive peptides and H2O2 elicit their cellular responses. However, a role for the insulin-like growth factor type-1 receptor (IGF-1R) transactivation in mediating the effects of angiotensin II (Ang II) and H2O2 in vascular smooth muscle cells from different artery types have also been recently recognized. By using a series of pharmacological inhibitors of various growth factor receptor tyrosine kinases and a direct analysis of the phosphorylation status of the beta-subunit of IGF-1R, a requirement of this growth factor receptor in Ang II and H2O2 response has been demonstrated.

Endothelin-1-induced signaling pathways in vascular smooth muscle cells.

Endothelin-1 (ET-1), a vasoactive peptide, is believed to contribute to the pathogenesis of vascular abnormalities such as hypertension, atherosclerosis, hypertrophy and restenosis. ET-1 elicits its biological effects through the activation of two receptor subtypes, ET-A and ET-B that belong to a large family of transmembrane guanine nucleotide-binding protein-coupled receptors (GPCRs). ET-1 receptor activation results in the stimulation of several signaling pathways including mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3-K) and protein kinase B (PKB).

Individual QTLs controlling quantitative variation in blood pressure inherited in a Mendelian mode.

We studied three possible genotypes at 10 well-defined blood pressure (BP) QTLs using congenic rat lines. The central question was whether the hypertensive or normotensive allele is dominant, or whether there is partial dominance. The congenic strains were employed to investigate the BP effects of alleles originating from normotensive rats in the background of hypertensive Dahl salt-sensitive (DSS) rats.