Effect of statin and angiotensin-converting enzyme inhibition on structural and hemodynamic alterations in autosomal dominant polycystic kidney disease model

Abstract

Zafar I, Tao Y, Falk S, McFann K, Schrier RW, Edelstein CL. Effect of statin and angiotensin-converting enzyme inhibition on structural and hemodynamic alterations in autosomal dominant polycystic kidney disease model. Am J Physiol Renal Physiol 293: F854-F859, 2007. First published June 20, 2007; doi:10.1152/ajprenal.00059.2007.-Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening hereditary disease and is the fourth most common cause of end-stage kidney disease. Preclinical studies to identify effective interventions to prevent or slow progression of PKD nephropathy are therefore direly needed. Heterozygous Han:SPRD rats are an autosomal dominant PKD model with many of the characteristics of AD-PKD in humans. In the present study, parameters known to antedate the decrease in renal function, namely, renal structure, renal blood flow (RBF), and mean arterial pressure (MAP), were evaluated with three different interventions, namely, HMG-CoA reductase inhibition with lovastatin, angiotensin-converting enzyme (ACE) inhibition with enalapril, and a combination of these two treatments. The statin therapy demonstrated structural and functional benefits, including increased RBF and decreased BUN, independently of a change in MAP, while the ACE inhibition therapy demonstrated structural benefit in association with a decrease in MAP. An enhancement of these protective interventions in this autosomal dominant PKD model was not demonstrated with the combined treatment.renal blood flow; renal structure; blood pressure A DECREASE IN RENAL BLOOD flow (RBF) by magnetic resonance imaging recently has been shown in patients with ADPKD to parallel the increase in total kidney volume and to precede the decline in glomerular filtration rate (GFR) (27). In a doubleblind crossover study in 10 normocholesterolemic ADPKD patients, treatment for 4 wk with 40 mg simvastatin vs. placebo demonstrated an increase in RBF and GFR (30). Other HMGCoA reductase inhibitors (i.e., statins) have been shown in animal models to ameliorate progression of nephropathy and to increase RBF (1, 12). The statin, cerivastatin, decreased blood pressure, serum creatinine, and albuminuria in rats transgenic for human renin and angiotensin with hypertension, cardiac hypertrophy, renal damage, and marked albuminuria (20).There is considerable evidence that the renin-angiotensin system (RAS) is activated in ADPKD patients. The plasma renin and aldosterone responses to posture and angiotensinconverting enzyme (ACE) inhibition were greater in ADPKD patients than patients with essential hypertension of comparable age, gender, blood pressure, renal function, and urinary sodium excretion (3). Angiotensinogen, ACE, angiotensin II type I (AT 1 ) receptor, and angiotensin II have been found within cysts and tubules of ADPKD kidneys, thus implicating intrarenal RAS (19). Immunoreactive renin also has been found in tubules and cyst fluid of ADPKD kidneys (26).The effect of statin therapy with lovastatin to diminish the severity of renal d...

Effect of Pravastatin on Total Kidney Volume, Left Ventricular Mass Index, and Microalbuminuria in Pediatric Autosomal Dominant Polycystic Kidney Disease

“…Experimental evidence in rats has shown that statins decrease the severity of functional and structural disease in ADPKD (13,14). Moreover, statins are of benefit for endothelial dysfunction (28)(29)(30), which is known to occur early in patients with ADPKD, even before the onset of hypertension (31).…”

“…In heterozygous male Han:SPRD rats, an animal model of ADPKD, lovastatin has been shown to reduce the severity of kidney disease as assessed by kidney size, volume density of cysts, and serum urea nitrogen concentration (13). Although the underlying mechanisms are not well understood, these renoprotective effects may be mediated by statin-related inhibition of G proteins with resultant decreased cell proliferation (14). Short-term (4-week) treatment of 10 normocholesterolemic normotensive adults with ADPKD with simvastatin resulted in increased RBF and GFR (10).…”

Targeting Cyst Initiation in ADPKD

“…These include the vasopressin receptor antagonists OPC-31260 and tolvaptan, 1,2 which decrease cAMP production; the somatostatin analog octreotide 3 ; antagonists of the Cl Ϫ channel cystic fibrosis transmembrane conductance regulator 4,5 ; angiotensin-converting enzyme inhibitors 6,7 ; and small molecule inhibitors of the basolateral KCa3.1 K ϩ channel. 8 Other candidates include inhibitors of the inflammatory mediator TNF-␣, 9 cell growth regulators such as the mTOR antagonist rapamycin 10 ; and the antiproliferative cyclin-dependent kinase inhibitor roscovitine.…”

“…5 It is now known they also express dendritic cell markers and can indeed present antigen-one of the defining features of renal dendritic cells with broadly similar characteristics to dendritic cells in other tissues. [5][6][7][8][9][10] Studies in mice with fluorescently labeled dendritic cells show essentially all resident myeloid cells are dendritic, reveal their intimate connection with renal tubules through long processes kissing the epithelial cells, and thus are ideally positioned to sample reabsorbed antigens or receive activation signals from them. 6,7 Consequently, renal dendritic cells are the likely sentinals that sample renal antigens and present them to T cells.…”

“…[5][6][7][8][9][10] Studies in mice with fluorescently labeled dendritic cells show essentially all resident myeloid cells are dendritic, reveal their intimate connection with renal tubules through long processes kissing the epithelial cells, and thus are ideally positioned to sample reabsorbed antigens or receive activation signals from them. 6,7 Consequently, renal dendritic cells are the likely sentinals that sample renal antigens and present them to T cells. The endocytosed antigen is processed in one of two ways: either in endocytic compartments to create peptides that are loaded on to MHC class II molecules that…”