atrial-natriuretic-factor 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

In order to investigate the effects of atrial natriuretic polypeptides (ANP) on hypertensive glomerular lesions, ANP was administered intravenously by osmotic minipumps to 20 15-week-old male spontaneously hypertensive rats (SHRs) in a sustained hypertensive stage. ANP was infused at the rate of 100 ng/hour/rat (the ANP group). Saline was similarly administered to 19 age-matched SHRs (the control group). The rats were sacrificed on the seventh day. Semiquantitative evaluation of the renal tissue revealed no significant difference in glomerular sclerosis between the 2 groups. However, segmental hyalinosis in glomeruli was more accentuated in the ANP group than in the control group. As it is suggested that hyalinosis in glomeruli is related to the elevated intracapillary pressure, the results of the present work were in accordance with reports that ANP increases glomerular capillary pressure by preglomerular vasodilation and postglomerular vasoconstriction. It should be determined whether endogenous ANP works as an aggravating factor for glomerular injuries in the natural course of hypertension.

Topics: Animals; Atrial Natriuretic Factor; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Hypertension; Infusion Pumps; Kidney Glomerulus; Male; Rats; Rats, Inbred SHR