• ADPKD
• Han:SPRD rat
• PKD/Mhm rat
• PKDR1
• anks6
• ciliopathies
• nephronopthisis
• polycystic kidney disease

• ADPKD
• Cardiomyopathies
• Cardiovascular diseases
• Hypertension
• Left ventricular hypertrophy
• Valvular heart disease

• Humans
• Polycystic Kidney, Autosomal Dominant/complications
• Cardiovascular Diseases/epidemiology
• Hypertension/complications
• Kidney
• Cysts/complications

• Cystic fibrosis
• Hedgehog pathway
• JAK2 protein
• MAP kinase signaling system
• PPAR gamma
• Platelet endothelial cell adhesion molecule-1
• Polycystin-1

Blood pressure (BP) control is one of the most important treatments of Autosomal dominant polycystic kidney disease (ADPKD). The comparative efficacy of antihypertensive treatments in ADPKD patients is inconclusive.

Network meta-analysis was used to evaluate randomized controlled trials (RCT) which investigated antihypertensive treatments in ADPKD. PubMed, Embase, Ovid, and Cochrane Collaboration were searched. The primary outcome was estimated glomerular filtration rate (eGFR). Secondary outcomes were serum creatinine (Scr), urinary albumin excretion (UAE), systolic BP (SBP), diastolic BP (DBP), mean artery pressure (MAP) and left ventricular mass index (LVMI).

We included 10 RCTs with 1386 patients and six interventions: angiotensin-converting enzyme inhibitors (ACEI), Angiotensin II receptor blocker (ARB), combination of ACEI and ARB, calcium channel blockers (CCB), β-blockers and dilazep. There was no difference of eGFR in all the treatments in both network and direct comparisons. No significant differences of Scr, SBP, DBP, MAP, and LVMI were found in network comparisons. However, ACEI significantly reduced SBP, DBP, MAP and LVMI when compared to CCB. Significantly increased UAE was observed in CCB compared with ACEI or ARB. Bayesian probability analysis found ARB ranked first in the surrogate measures of eGFR, UAE and SBP.

There is little evidence to detect differences of antihypertensive treatments on kidney disease progression in ADPKD patients. More RCTs will be needed in the future. Use of ARB may be an optimal choice in clinical practice.

• Pathology Section
• antihypertensive drug
• autosomal dominant
• glomerular filtration rate
• polycystic kidney disease
• urinary albumin excretion

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited monogenic kidney disease. Characterized by the development and growth of cysts that cause progressive kidney enlargement, it ultimately leads to end-stage renal disease. Approximately 85% of ADPKD cases are caused by mutations in the PKD1 gene, while mutations in the PKD2 gene account for the remaining 15% of cases. The PKD1 gene encodes for polycystin-1 (PC1), a large multi-functional membrane receptor protein able to regulate ion channel complexes, whereas polycystin-2 (PC2), encoded by the PKD2 gene, is an integral membrane protein that functions as a calcium-permeable cation channel, located mainly in the endoplasmic reticulum (ER). In the primary cilia of the epithelial cells, PC1 interacts with PC2 to form a polycystin complex that acts as a mechanosensor, regulating signaling pathways involved in the differentiation of kidney tubular epithelial cells. Despite progress in understanding the function of these proteins, the molecular mechanisms associated with the pathogenesis of ADPKD remain unclear. In this review we discuss how an imbalance between functional PC1 and PC2 proteins may disrupt calcium channel activities in the cilium, plasma membrane and ER, thereby altering intracellular calcium signaling and leading to the aberrant cell proliferation and apoptosis associated with the development and growth of renal cysts. Research in this field could lead to the discovery of new molecules able to rebalance intracellular calcium, thereby normalizing cell proliferation and reducing kidney cyst progression.

• Autosomal dominant polycystic kidney disease
• Calcium signaling
• cAMP
• Cell growth
• Non-capacitative calcium entry

• CaV1.2 L-type calcium channel
• Cystic kidney
• Modifier gene
• PKD
• Primary cilia

• autosomal dominant polycystic kidney disease
• endothelial dysfunction
• hypertension
• renin–angiotensin–aldosterone system
• treatment

The major sphingolipid metabolite, sphingosine‐1‐phosphate (S1P), has important biological functions. S1P serves as a ligand for a family of five G‐protein‐coupled receptors with distinct signaling pathways regulating important biological pathways. S1P induces renal fibrosis through an inflammatory pathway. However, its direct fibrosis‐inducing effect on the kidney has not been shown. The role of S1P as a direct mediator of renal fibrosis was investigated in normal rat kidney interstitial fibroblast (NRK‐49F) cells (in vitro) and kidneys of a unilateral ureteral obstruction (UUO) mouse model (in vivo). To clarify the role of S1P in renal fibrosis, we adopted nude UUO mice with immune response deficits. NRK‐49F cells were stimulated with various concentrations of exogenous S1P and FTY720 (a S1P receptor agonist) or N,N‐dimethylsphingosine (DMS; a sphingosine kinase inhibitor). C57BL6 and nude UUO mice were pretreated with FTY720, DMS, or saline. Expression levels of alpha‐smooth muscle actin (a‐SMA), E‐cadherin, collagen type 1 (COL1), collagen type 4 (COL4), tissue inhibitor of matrix metalloproteinase‐1 (TIMP1), and plasminogen activator inhibitor‐1 (PAI1) were examined. S1P stimulated fibrosis in NRK‐49F cells and UUO mice. Increased a‐SMA, COL1, COL4, TIMP1, and PAI1 and decreased E‐cadherin expression levels were observed in both the S1P‐stimulated cells and UUO mice. Nude UUO mouse kidneys expressed fibrotic markers. Fibrotic changes were successfully induced in both UUO and nude UUO mice, evident through prominent fibronectin and COL1 staining. These S1P‐induced fibrotic changes were suppressed by FTY720 and DMS both in vitro and in vivo. Thus, S1P essentially and directly mediates renal fibrosis.

Sphingosine‐1‐phosphate (S1P) stimulated fibrosis both in vitro and in vivo. Fibrotic changes were successfully induced in both unilateral ureteral obstruction (UUO) and nude mice with UUO. These results suggest that S1P is a pivotal fibrotic mediator in renal fibrosis that acts, in part, through direct fibrotic effects.

• DMS
• FTY720
• UUO
• renal fibrosis
• sphingosine‐1‐phosphate

Cardiovascular (CV) complications are the major cause of death in autosomal-dominant polycystic kidney disease (ADPKD) patients. Hypertension is common in these patients even before the onset of renal insufficiency. Blood pressure (BP) elevation is a key factor in patient outcome, mainly owing to the high prevalence of target organ damage together with a poor renal prognosis when BP is increased. Many factors have been implicated in the pathogenesis of hypertension, including the renin–angiotensin–aldosterone system (RAAS) stimulation. Polycystin deficiency may also contribute to hypertension because of its potential role in regulating the vascular tone. Early diagnosis and treatment of hypertension improve the CV and renal complications of this population. Ambulatory BP monitoring is recommended for prompt diagnosis of hypertension. CV risk assessment is mandatory. Even though a nonpharmacological approach should not be neglected, RAAS inhibitors are the cornerstone of hypertension treatment. Calcium channel blockers (CCBs) should be avoided unless resistant hypertension is present. The BP should be <140/90 mmHg in all ADPKD patients and a more intensive control (<135/85 mmHg) should be pursued as soon as microalbuminuria or left ventricle hypertrophy is present.

• ambulatory blood pressure monitoring
• blood pressure profile
• cardiovascular risk
• polycystic kidney disease
• renal size

• Cyclic AMP/antagonists & inhibitors
• Cyclic AMP/metabolism
• Drug Therapy, Combination
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/metabolism
• Humans
• Polycystic Kidney, Autosomal Dominant/drug therapy
• Polycystic Kidney, Autosomal Dominant/metabolism
• Signal Transduction/drug effects
• TOR Serine-Threonine Kinases/antagonists & inhibitors
• TOR Serine-Threonine Kinases/metabolism