The Link between Autosomal Dominant Polycystic Kidney Disease and Chromosomal Instability: Exploring the Relationship.

In autosomal dominant polycystic kidney disease (ADPKD) with germline mutations in a or gene, innumerable cysts develop from tubules, and renal function deteriorates. Second-hit somatic mutations and renal tubular epithelial (RTE) cell death are crucial features of cyst initiation and disease progression. Here, we use established RTE lines and primary ADPKD cells with disease-associated mutations to investigate genomic instability and DNA damage responses.

Aberrant DNA damage response and DNA repair pathway in high glucose conditions.

Background: Higher cancer rates and more aggressive behavior of certain cancers have been reported in populations with diabetes mellitus. This association has been attributed in part to the excessive reactive oxygen species generated in diabetic conditions and to the resulting oxidative DNA damage. It is not known, however, whether oxidative stress is the only contributing factor to genomic instability in patients with diabetes or whether high glucose directly also affects DNA damage and repair pathways.

Expression of Nek1 during kidney development and cyst formation in multiple nephron segments in the Nek1-deficient kat2J mouse model of polycystic kidney disease.

Background: Neks, mammalian orthologs of the fungal protein kinase never-in-mitosis A, have been implicated in the pathogenesis of polycystic kidney disease. Among them, Nek1 is the primary protein inactivated in kat2J mouse models of PKD.

Result: We report the expression pattern of Nek1 and characterize the renal cysts that develop in kat2J mice.

Increased Nek1 expression in renal cell carcinoma cells is associated with decreased sensitivity to DNA-damaging treatment.

Renal cell carcinoma (RCC) is a heterogeneous disease with resistance to systemic chemotherapy. Elevated expression of multiple drug resistance (MDR) has been suggested to be one of the mechanisms for this resistance. Here, we provide an alternative mechanism to explain RCC's resistance to chemotherapy-induced apoptosis.

Key diagnostic features of granulomatous interstitial nephritis due to Encephalitozoon cuniculi in a lung transplant recipient.

Microsporidia are increasingly recognized as opportunistic pathogens in immunocompromised organ transplant recipients (OTR). Disseminated infection due to Encephalitozoon sp. is reported mainly in human immunodeficiency virus (HIV)-positive patients and rarely in HIV-negative OTR.

Nek1 kinase functions in DNA damage response and checkpoint control through a pathway independent of ATM and ATR.

Never-in-mitosis A related protein kinase 1 (Nek1) is involved early in a DNA damage sensing/repair pathway. We have previously shown that cells without functional Nek1 fail to activate the more distal kinases Chk1 and Chk2 and fail to arrest properly at G1/S or M-phase checkpoints in response to DNA damage. As a consequence, foci of damaged DNA in Nek1 null cells persist long after the instigating insult, and Nek1 null cells develop unstable chromosomes at a rate much higher than identically cultured wild type cells.

Mutation of NIMA-related kinase 1 (NEK1) leads to chromosome instability.

Background: NEK1, the first mammalian ortholog of the fungal protein kinase never-in-mitosis A (NIMA), is involved early in the DNA damage sensing/repair pathway. A defect in DNA repair in NEK1-deficient cells is suggested by persistence of DNA double strand breaks after low dose ionizing radiation (IR). NEK1-deficient cells also fail to activate the checkpoint kinases CHK1 and CHK2, and fail to arrest properly at G1/S or G2/M-phase checkpoints after DNA damage.

Phosphorylation by Nek1 regulates opening and closing of voltage dependent anion channel 1.

VDAC1 is a key component of the mitochondrial permeability transition pore. To initiate apoptosis and certain other forms of cell death, mitochondria become permeable such that cytochrome c and other pre-apoptotic molecules resident inside the mitochondria enter the cytosol and activate apoptotic cascades. We have shown recently that VDAC1 interacts directly with never-in-mitosis A related kinase 1 (Nek1), and that Nek1 phosphorylates VDAC1 on Ser193 to prevent excessive cell death after injury.

Nek1 regulates cell death and mitochondrial membrane permeability through phosphorylation of VDAC1.

The mammalian NIMA-related protein kinase 1 (Nek1) is important for keeping cells alive after DNA damage, but the mechanism by which injured cells die without functional Nek1 has not yet been demonstrated. Here we show that Nek1 regulates the pathway to mitochondrial cell death through phosphorylation of voltage dependent anion channel 1 (VDAC1) on serine 193. Nek1 associates with VDAC1 in a yeast two-hybrid system, as well as by GST pull-down assays and by reciprocal immunoprecipitation.

Never-in-mitosis related kinase 1 functions in DNA damage response and checkpoint control.

Nek1, the first mammalian ortholog of the fungal protein kinase never in mitosis A, is involved early in the DNA damage sensing/repair pathway after ionizing radiation. Here we extend this finding by showing that Nek1 localizes to nuclear foci of DNA damage in response to many different types of damage in addition to IR. Untransformed cells established from kat2J/Nek1(-/-) mice fail to arrest properly at G(1)/S and M-phase checkpoints in response to DNA damage.

Raptor-rictor axis in TGFbeta-induced protein synthesis.

Transforming growth factor-beta (TGFbeta) stimulates pathological renal cell hypertrophy for which increased protein synthesis is critical. The mechanism of TGFbeta-induced protein synthesis is not known, but PI 3 kinase-dependent Akt kinase activity is necessary. We investigated the contribution of downstream effectors of Akt in TGFbeta-stimulated protein synthesis.

Tuberin regulates the DNA repair enzyme OGG1.

The tuberous sclerosis complex (TSC) is caused by defects in one of two tumor suppressor genes, TSC-1 or TSC-2. The TSC-2 gene encodes tuberin, a protein involved in the pathogenesis of kidney tumors, both angiomyolipomas and renal cell carcinomas. We investigated a potential role for tuberin in regulating a key DNA repair pathway.

Human monocytic ehrlichiosis in a renal transplant patient.

Human ehrlichiosis is an emerging pathogen in immunocompromised patients, potentially leading to increased morbidity compared to immunocompetent patients. A high index of suspicion is imperative and early treatment with doxycycline can be life-saving. We report the case of an immunosuppressed renal transplant patient who was diagnosed with human monocytic ehrlichiosis and successfully treated with doxycycline.

NIMA-related protein kinase 1 is involved early in the ionizing radiation-induced DNA damage response.

Cellular functions of the NimA-related mammalian kinase Nek1 have not been demonstrated to date. Here we show that Nek1 is involved early in the DNA damage response induced by ionizing radiation (IR) and that Nek1 is important for cells to repair and recover from DNA damage. When primary or transformed cells are exposed to IR, Nek1 kinase activity is increased within 4 minutes, and Nek1 expression is up-regulated shortly thereafter and sustained for hours.

Prediction of GFR in liver transplant candidates.

Background: Kidney function frequently is impaired in patients with cirrhosis; however, glomerular filtration rate (GFR) is difficult to estimate in these patients by using standard clinical markers. The aim of our study is to compare GFR calculated from renal clearance of iodine 125-labeled iothalamate ((125)I-iothalamate) with the plasma decay technique and the Modification of Diet in Renal Disease (MDRD) and Cockroft-Gault (CG) prediction equations.

Methods: We performed a cross-sectional study of patients with liver cirrhosis being evaluated for transplantation (50% Child's class C); 89% had ascites or edema and 44% were men aged 55 +/- 2 years.

Activation of cyclin D1-Cdk4 and Cdk4-directed phosphorylation of RB protein in diabetic mesangial hypertrophy.

To determine the role of cell-cycle proteins in regulating pathological renal hypertrophy, diabetes was induced in mice expressing a human retinoblastoma (RB) transgene and in wild-type littermates. Whole-kidney and glomerular hypertrophy caused by hyperglycemia was associated with specific G1 phase cell-cycle events: early and sustained increase in expression of cyclin D1 and activation of cyclin D1-cdk4 complexes, but no change in expression of cyclin E or cdk2 activity. Overexpression of RB alone likewise caused hypertrophy and increased only cyclin D1-cdk4 activity; these effects were not further augmented by high glucose.

Phosphorylation of the mitotic regulator protein Hec1 by Nek2 kinase is essential for faithful chromosome segregation.

Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the G(2)/M phase. Hec1 localizes to kinetochores, and its inactivation either by genetic deletion or antibody neutralization leads to severe and lethal chromosomal segregation errors, indicating that Hec1 plays a critical role in chromosome segregation. The mechanisms by which Hec1 is regulated, however, are not known.

Renal adaptation to the failing heart.

Preview Selection of therapy for patients with systolic cardiac dysfunction must be predicated on careful assessment of the delicate interplay between the failing heart and the state of effective circulating blood volume. In this article, the authors discuss the drugs that improve systolic function and effective circulating volume and, ultimately, enhance tissue perfusion in vital organs such as the kidney. A companion article on page 141 explains the renal and neurohumoral events that occur in patients with systolic heart failure.

Renal adaptation to the failing heart.

Preview In patients with congestive heart failure, a diversity of neurohumoral and renal responses are involved in the maintenance of effective circuiting blood volume. The major clinical consequences of these responses are edema formation and, ultimately, decreased renal perfusion. In this article, the authors review the mechanisms that affect renal function in patients with systolic heart failure.