cyclic-gmp and Glomerulosclerosis--Focal-Segmental

Glomerular podocytes play a key role in proteinuric diseases. Accumulating evidence suggests that cGMP signaling has podocyte protective effects. The major source of cGMP generation in podocytes is natriuretic peptides. The natriuretic peptide clearance receptor (NPRC) binds and degrades natriuretic peptides. As a result, NPRC inhibits natriuretic peptide-induced cGMP generation. To enhance cGMP generation in podocytes, we blocked natriuretic peptide clearance using the specific NPRC ligand ANP(4-23). We then studied the effects of NPRC blockade in both cultured podocytes and in a mouse transgenic (TG) model of focal segmental glomerulosclerosis (FSGS) created in our laboratory. In this model, a single dose of the podocyte toxin puromycin aminonucleoside (PAN) causes robust albuminuria in TG mice, but only mild disease in non-TG animals. We found that natriuretic peptides protected cultured podocytes from PAN-induced apoptosis, and that ANP(4-23) enhanced natriuretic peptide-induced cGMP generation in vivo. PAN-induced heavy proteinuria in vehicle-treated TG mice, and this increase in albuminuria was reduced by treatment with ANP(4-23). Treatment with ANP(4-23) also reduced the number of mice with glomerular injury and enhanced urinary cGMP excretion, but these differences were not statistically significant. Systolic BP was similar in vehicle and ANP(4-23)-treated mice. These data suggest that: 1. Pharmacologic blockade of NPRC may be useful for treating glomerular diseases such as FSGS, and 2. Treatment outcomes might be improved by optimizing NPRC blockade to inhibit natriuretic peptide clearance more effectively.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; Cell Line; Cyclic GMP; Female; Glomerulosclerosis, Focal Segmental; Male; Mice; Natriuretic Peptides; Peptide Fragments; Podocytes; Proteinuria; Receptors, Atrial Natriuretic Factor

The kidney's role in the pathogenesis of salt-induced hypertension remains unclear. However, it has been suggested that inherited morphological renal abnormalities may cause hypertension. We hypothesized that functional, not morphological, derangements in Dahl salt-sensitive rats' kidneys cause NaCl retention that leads to hypertension accompanied by renal pathologic changes and proteinuria.. We studied hemodynamic, renal morphologic, and biochemical differences in Dahl salt-resistant and Dahl salt-sensitive rats fed low (0.05-0.23% NaCl) or elevated (1% NaCl) salt diets.. We found similar hemodynamics, equal numbers of glomeruli, normal renal medullary interstitial cells and their osmiophilic granules, and cortical morphology in normotensive Dahl salt-resistant and Dahl salt-sensitive rats fed low dietary salt. Furthermore, aldosterone secretion, caused by angiotensin II infusion in normotensive rats fed 0.23% NaCl, was significantly less in Dahl salt-sensitive than Dahl salt-resistant rats. Increasing NaCl to 1% caused renal vasoconstriction without changing cyclic GMP excretion in Dahl salt-sensitive rats; in Dahl salt-resistant rats, cyclic GMP increased markedly and renal vascular resistance remained unchanged. On 1% NaCl for 9 months, Dahl salt-sensitive rats developed marked hypertension, severe renal vasoconstriction, glomerulosclerosis, tubulointerstitial abnormalities, and marked proteinuria; hypertension resulted from increased total peripheral resistance, as occurs in essential hypertensive humans. No hemodynamic or renal pathologic changes occurred in Dahl salt-resistant rats, and proteinuria was minimal.. We conclude that renal functional, not morphological, abnormalities cause salt sensitivity in Dahl rats.

Topics: Aldosterone; Angiotensin II; Animals; Blood Pressure; Cyclic GMP; Diastole; Dose-Response Relationship, Drug; Fibrosis; Glomerulosclerosis, Focal Segmental; Hemodynamics; Hypertension; Kidney; Kidney Glomerulus; Kidney Medulla; Organ Size; Proteinuria; Rats; Rats, Inbred Dahl; Sodium; Sodium Chloride, Dietary; Systole; Time Factors; Vascular Resistance; Vasoconstriction

Chronic renal disease is associated with oxidative stress and reduced nitric oxide availability which, in turn, promotes hypertension and further progression of renal damage. Most actions of nitric oxide are mediated by cyclic 3',5' guanosine monophosphate (cGMP) which is rapidly degraded by phosphodiesterases (PDE). Therefore, we investigated if inhibition of PDE-5 would retard the progression of chronic renal failure.. We studied rats with 5/6 nephrectomy treated with sildenafil (2.5 mg/kg(-1)/day(-1)) in two experimental protocols. In the first protocol, we started sildenafil therapy immediately after renal ablation and continued treatment for 8 weeks. Control groups consisted of rats with renal ablation treated with drug-free vehicle and sham-operated rats with and without sildenafil treatment.. In these studies, sildenafil treatment prevented hypertension and deterioration of renal function, reduced histologic damage, inflammation and apoptosis, delayed the onset of proteinuria, and preserved renal capillary integrity. In the second protocol we compared sildenafil with losartan (7.5 mg/kg(-1)/day(-1)) and the combination of both drugs in established renal disease, starting these drugs 4 weeks after 5/6 nephrectomy. Delayed sildenafil treatment failed to improve proteinuria and glomerulosclerosis but ameliorated hypertension and azotemia.. These observations suggest that currently available PDE-5 inhibitors have potential clinical value in the treatment of chronic renal disease.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Apoptosis; Blood Pressure; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Glomerulosclerosis, Focal Segmental; Kidney Function Tests; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Sildenafil Citrate; Sulfones

1. The present experiments were designed to investigate the role of asymmetrical NG,NG-dimethyl-L-arginine (ADMA) in causing hypertension associated with the focal and segmental glomerulosclerosis (FSGS) produced by a single bolus of puromycin aminonucleoside (PAN) and successive injection of protamine for 7 days in rats which had undergone unilateral nephrectomy. 2. After the unilateral nephrectomy, and administering PAN and protamine, histological examinations of the kidney revealed a typical FSGS, that is, evident abnormalities including segmental mesangial proliferation, obliteration of glomerular capillary lumens and adhesions between the glomerulus and Bowman's capsule could be observed. Changes in the glomerular epithelial cells consisted of the swelling with bleb formation. 3. In the FSGS rats, urine volume and urinary protein were significantly (P<0.05 and P<0.005) increased throughout 4-week experimental period, while the creatinine clearance was significantly (P<0.005) and transiently decreased, and recovered 4 weeks later. These changes were associated with the sustained elevation of the systolic blood pressure. 4. ADMA levels in aortic endothelial cells, plasma and urine were significantly (P<0.05 and P<0.005) increased in the FSGS rats, but the level in the kidney remained unchanged. 5. The basal level and net production of cyclic GMP in the aortic vessel wall with endothelium when stimulated by norepinephrine and acetylcholine were significantly (P<0.05 and P<0.01) attenuated in the FSGS rats. 6. There were significant and positive correlations between systolic blood pressure (y) and ADMA levels (x) in endothelial cells (y=4.43x+122.2, r=0.979, P<0.0001), plasma (y=0.10x+71.9, r=0.921, P<0.001) and urine (y=0.48x+126.9, r =0.699, P<0.005), but not significant in the kidney (y=0.06x+102.7, r=0.252, NS). 7. These findings suggest that ADMA as an endogenous inhibitor of NO synthesis may play an important role for the pathogenesis in the hypertension associated with the experimental FSGS in the rat.

Topics: Animals; Arginine; Blood Pressure; Body Weight; Cyclic GMP; Endothelium; Glomerulosclerosis, Focal Segmental; Hypertension; Kidney; Male; Nitrous Oxide; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley

To investigate the effects of subpressor doses of angiotensin II (Ang II) on the progression of renal injuries in Dahl salt-sensitive (Dahl-S) rats with hypertension.. Rats were fed a high-salt (4% NaCl) diet and given an Ang II infusion (10 or 50 ng/kg per min, subcutaneously) for 4 weeks.. The plasma Ang II concentration achieved in the high-dose Ang II infusion was lower than that in low-salt (0.3% NaCl) normotensive rats. The Ang II infusion did not affect systolic blood pressure, cardiac hypertrophy or weight of thoracic aorta. However, the high-dose Ang II infusion increased proteinuria by 58%, enhanced the urinary N-acetyl-beta-D-glucosaminase index by 77% and reduced the glomerular filtration rate by 37%. The impaired renal function was associated with a progression of glomerulosclerotic lesions. Neither tubular nor arterial lesions were exacerbated. The infusion did not influence prostacyclin production or urinary cyclic GMP excretion.. A subpressor dose of Ang II infusion impairs renal function with progression of glomerulosclerosis, and these alterations may be due to increased susceptibility of the glomerulus in Dahl-S rats to Ang II-induced injuries. Such a mechanism might underlie a predisposition to hypertension-induced organ damage seen in Dahl-S rats with salt-induced hypertension.

Topics: Angiotensin II; Animals; Cyclic AMP; Cyclic GMP; Eicosanoids; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Hemodynamics; Hypertension; Injections, Subcutaneous; Kidney; Lipid Peroxides; Radioimmunoassay; Rats