Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis.

Prolyl hydroxylase domain enzyme inhibitors (PHDIs) stabilize hypoxia-inducible factors (HIFs), and are protective in models of acute ischemic and inflammatory kidney disease. Whether PHDIs also confer protection in chronic inflammatory kidney disease models remains unknown. Here we investigated long-term effects of PHDI treatment in adenine-induced nephropathy as a model for chronic tubulointerstitial nephritis.

HIF-1α promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations of the PKD1 gene and characterized by growth of bilateral renal cysts. Cyst growth is accompanied by regional hypoxia and induction of hypoxia-inducible factor (HIF)-1α in cyst-lining epithelial cells. To determine the relevance of HIF-1α for cyst growth in vivo we used an inducible kidney epithelium-specific knockout mouse to delete Pkd1 at postnatal day 20 or 35 to induce polycystic kidney disease of different severity and analyzed the effects of Hif-1α co-deletion and HIF-1α stabilization using a prolyl-hydroxylase inhibitor.

Mild Salt-Sensitive Hypertension in Genetically Determined Low Nephron Number is Associated with Chloride but Not Sodium Retention.

Background/aims: One potential pathomechanism how low nephron number leads to hypertension in later life is altered salt handling. We therefore evaluated changes in electrolyte and water content in wildtype (wt) and GDNF+/- mice with a 30% reduction of nephron number.

Methods: 32 GDNF+/- and 36 wt mice were fed with low salt (LSD, 0.

Hypoxia inducible factor stabilization improves defective ischemia-induced angiogenesis in a rodent model of chronic kidney disease.

Chronic kidney disease (CKD) is associated with increased risk and worse prognosis of cardiovascular disease, including peripheral artery disease. An impaired angiogenic response to ischemia may contribute to poor outcomes of peripheral artery disease in patients with CKD. Hypoxia inducible factors (HIF) are master regulators of angiogenesis and therefore represent a promising target for therapeutic intervention.

Hypoxia inhibits nephrogenesis through paracrine Vegfa despite the ability to enhance tubulogenesis.

Reduced nephron number predisposes to hypertension and kidney disease. Interaction of the branching ureteric bud and surrounding mesenchymal cells determines nephron number. Since oxygen supply may be critical for intrauterine development, we tested whether hypoxia and hypoxia-inducible factor-1α (HIF-1α) influence nephrogenesis.

Kidney injury is independent of endothelial HIF-1α.

Unlabelled: Hypoxia-inducible transcription factors (HIFs) control cellular adaptation to low oxygen. In the kidney, activation of HIF is beneficial during injury; however, the specific contribution of HIF-1α in renal endothelial cells (EC) remains elusive. Since EC display tissue-specific heterogeneity, we investigated how HIF-1α affects key functions of glomerular EC in vitro and its contribution to renal development and pathophysiological adaptation to acute or chronic renal injury in vivo.

Darbepoetin alpha reduces oxidative stress and chronic inflammation in atherosclerotic lesions of apo E deficient mice in experimental renal failure.

Background: Cardiovascular morbidity and mortality is very important in patients with chronic renal failure. This occurs even in mild impairment of renal function and may be related to oxidative stress and chronic inflammation. The nephrectomized apo E knockout mouse is an accepted model for evaluating atherosclerosis in renal dysfunction.

Renal protection by low dose irbesartan in diabetic nephropathy is paralleled by a reduction of inflammation, not of endoplasmic reticulum stress.

Diabetes can disrupt endoplasmic reticulum (ER) homeostasis which leads to ER stress. ER stress-induced renal apoptosis seems to be involved in the development of diabetic nephropathy. The present study was designed to investigate the contribution of reduced ER stress to the beneficial effects of an angiotensin receptor blocker.

Hypoxia-inducible factor-1α causes renal cyst expansion through calcium-activated chloride secretion.

Polycystic kidney diseases are characterized by numerous bilateral renal cysts that continuously enlarge and, through compression of intact nephrons, lead to a decline in kidney function over time. We previously showed that cyst enlargement is accompanied by regional hypoxia, which results in the stabilization of hypoxia-inducible transcription factor-1α (HIF-1α) in the cyst epithelium. Here we demonstrate a correlation between cyst size and the expression of the HIF-1α-target gene, glucose transporter 1, and report that HIF-1α promotes renal cyst growth in two in vitro cyst models-principal-like MDCK cells (plMDCKs) within a collagen matrix and cultured embryonic mouse kidneys stimulated with forskolin.

Hypoxia regulates the sperm associated antigen 4 (SPAG4) via HIF, which is expressed in renal clear cell carcinoma and promotes migration and invasion in vitro.

Hypoxia leads to the upregulation of a variety of genes mediated largely via the hypoxia inducible transcription factor (HIF). Prominent HIF-regulated target genes such as the vascular endothelial growth factor (VEGF), the glucose transporter 1 (Glut-1), or erythropoietin (EPO) help to assure survival of cells and organisms in a low oxygenated environment. Here, we are the first to report the hypoxic regulation of the sperm associated antigen 4 (SPAG4).

Tubulointerstitial de novo expression of the α8 integrin chain in a rodent model of renal fibrosis--a potential target for anti-fibrotic therapy?

In the normal kidney, the α8 integrin chain is expressed only on mesangial cells and vascular smooth muscle cells. α8 integrin ligates several matrix molecules including fibronectin, osteopontin and fibrillin-1. Recently, we detected de novo expression of α8 integrin on epithelial cells in renal cysts.

Selective stabilization of HIF-1α in renal tubular cells by 2-oxoglutarate analogues.

The role of proximal versus distal tubular injury in the pathogenesis of acute kidney injury (AKI) is debatable. Inhibition of prolyl hydroxylases that regulate the degradation of hypoxia-inducible transcription factors (HIFs) is a promising therapeutic approach to optimize energy preservation under hypoxia and has successfully been applied to protect kidney structure and function in AKI models. Presently used prolyl hydroxylase inhibitors are lipophilic 2-oxoglutarate analogues (2OGAs) that are widely taken up in cells of most organs.

Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts.

The Hypoxia-inducible transcription Factor (HIF) represents an important adaptive mechanism under hypoxia, whereas sustained activation may also have deleterious effects. HIF activity is determined by the oxygen regulated α-subunits HIF-1α or HIF-2α. Both are regulated by oxygen dependent degradation, which is controlled by the tumor suppressor "von Hippel-Lindau" (VHL), the gatekeeper of renal tubular growth control.

Hypoxia-inducible transcription factors stabilization in the thick ascending limb protects against ischemic acute kidney injury.

Hypoxia-inducible transcription factors (HIF) protect cells against oxygen deprivation, and HIF stabilization before ischemia mitigates tissue injury. Because ischemic acute kidney injury (AKI) often involves the thick ascending limb (TAL), modulation of HIF in this segment may be protective. Here, we generated mice with targeted TAL deletion of the von Hippel-Lindau protein (Vhl), which mediates HIF degradation under normoxia, using Tamm-Horsfall protein (Thp)-driven Cre expression.

The Raf kinase inhibitor PLX5568 slows cyst proliferation in rat polycystic kidney disease but promotes renal and hepatic fibrosis.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure. Aberrant epithelial cell proliferation is a major cause of progressive cyst enlargement in ADPKD. Since activation of the Ras/Raf signaling system has been detected in cyst-lining epithelia, inhibition of Raf kinase has been proposed as an approach to retard the progression of ADPKD.

Effect of the plasminogen-plasmin system on hypertensive renal and cardiac damage.

Background: The plasminogen-plasmin system affects tissue fibrosis, presumably by interacting with metalloproteinases (MMPs) and macrophage recruitment. This study tests the influence of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPa) on angiotensin II-mediated hypertensive kidney and heart injury.

Method: Hypertension was induced by continuous angiotensin II (Ang II) infusion via osmotic mini-pumps over 4 weeks.

The GTPase RAB20 is a HIF target with mitochondrial localization mediating apoptosis in hypoxia.

Hypoxia is a common pathogenic stress, which requires adaptive activation of the Hypoxia-inducible transcription factor (HIF). In concert transcriptional HIF targets enhance oxygen availability and simultaneously reduce oxygen demand, enabling survival in a hypoxic microenvironment. Here, we describe the characterization of a new HIF-1 target gene, Rab20, which is a member of the Rab family of small GTP-binding proteins, regulating intracellular trafficking and vesicle formation.

Factor inhibiting HIF limits the expression of hypoxia-inducible genes in podocytes and distal tubular cells.

The two hypoxia-inducible factors (HIF-1α and HIF-2α) are transcription factors that regulate the response to hypoxia. Recently, the factor inhibiting HIF (FIH1) was identified as a molecular oxygen-dependent dioxygenase that blunts the transcriptional activity of HIF and has also been implicated in HIF-dependent and -independent hypoxia responses. Interestingly, HIF accumulation in the kidney has been shown to confer renal protection and to also cause glomerular injury or enhance renal fibrosis.

Evidence for a lack of a direct transcriptional suppression of the iron regulatory peptide hepcidin by hypoxia-inducible factors.

Background: Hepcidin is a major regulator of iron metabolism and plays a key role in anemia of chronic disease, reducing intestinal iron uptake and release from body iron stores. Hypoxia and chemical stabilizers of the hypoxia-inducible transcription factor (HIF) have been shown to suppress hepcidin expression. We therefore investigated the role of HIF in hepcidin regulation.

HIF-prolyl hydroxylases in the rat kidney: physiologic expression patterns and regulation in acute kidney injury.

Hypoxia-inducible transcription factors (HIFs) play important roles in the response of the kidney to systemic and regional hypoxia. Degradation of HIFs is mediated by three oxygen-dependent HIF-prolyl hydroxylases (PHDs), which have partially overlapping characteristics. Although PHD inhibitors, which can induce HIFs in the presence of oxygen, are already in clinical development, little is known about the expression and regulation of these enzymes in the kidney.

Statin treatment reduces glomerular inflammation and podocyte damage in rat deoxycorticosterone-acetate-salt hypertension.

Objective: We examined the effects of fluvastatin treatment on the development of kidney injury in experimental deoxycorticosterone-acetate (DOCA)-salt hypertension.

Methods: Male Sprague-Dawley rats underwent unilateral nephrectomy and received subcutaneous DOCA pellets as well as 1% NaCl for drinking. Simultaneously, rats were treated with 5 mg/kg per day fluvastatin, or solvent only for 6 weeks.

Blood pressure versus direct mineralocorticoid effects on kidney inflammation and fibrosis in DOCA-salt hypertension.

Objective: We examined the contribution of high blood pressure versus direct mineralocorticoid effects to the progression of kidney inflammation and fibrosis in established experimental deoxycorticosterone-acetate (DOCA)-salt hypertension.

Methods: Male Sprague-Dawley rats underwent unilateral nephrectomy and received subcutaneous DOCA pellets as well as 1% NaCl for drinking. After 4 weeks of DOCA-salt hypertension, rats were either killed (n = 6), or treated with a non-hypotensive dose of spironolactone (n = 7) or triple therapy (hydrochlorothiazide, reserpine and hydralazine, n = 8) to normalize blood pressure or with vehicle (n = 19) for two further weeks.

Hypertension induces somatic cellular senescence in rats and humans by induction of cell cycle inhibitor p16INK4a.

There is increasing evidence for a role of somatic cellular senescence in physiological aging but also in injury and disease. Cell cycle inhibitor p16(INK4a) is the key mediator for stress and aberrant signaling induced senescence. Here we report that elevated blood pressure markedly induced p16(INK4a) expression in rat kidneys and hearts, as well as in human kidneys.

HIF activation protects from acute kidney injury.

The contribution of hypoxia to cisplatin-induced renal tubular injury is controversial. Because the hypoxia-inducible factor (HIF) pathway is a master regulator of adaptation to hypoxia, we measured the effects of cisplatin on HIF accumulation in vitro and in vivo, and tested whether hypoxic preconditioning is protective against cisplatin-induced injury. We found that cisplatin did not stabilize HIF-1alpha protein in vitro or in vivo under normoxic conditions.

(Pro)renin receptor peptide inhibitor "handle-region" peptide does not affect hypertensive nephrosclerosis in Goldblatt rats.

The (pro)renin receptor [(P)RR], a new component the renin-angiotensin system, was cloned recently. The (P)RR promotes direct mitogen-activated protein kinase signaling and nonproteolytic prorenin activation. We investigated the role of a (P)RR blocker, a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP), on target organ damage in renovascular hypertensive 2-kidney, 1-clip (2K1C) rats.