natriuretic-peptide--brain and Ureteral-Obstruction

Ureteral obstruction with subsequent hydronephrosis is a common clinical complication. Downregulation of renal sodium transporters in obstructed kidneys could contribute to impaired urinary concentrating capability and salt waste following the release of a ureteral obstruction. The current study was undertaken to investigate the role of mitochondrial complex-1 inhibition in modulating sodium transporters in obstructive kidney disease. Following unilateral ureteral obstruction (UUO) for 7 days, a global reduction of sodium transporters, including NHE3, α-Na-K-ATPase, NCC, NKCC2, p-NKCC2, ENaCα, and ENaCγ, was observed, as determined via qRT-PCR and/or Western blotting. Interestingly, inhibition of mitochondrial complex-1 by rotenone markedly reversed the downregulation of NKCC2, p-NKCC2, and ENaCα. In contrast, other sodium transporters were not affected by rotenone. To study the potential mechanisms involved in mediating the effects of rotenone on sodium transporters, we examined a number of known sodium modulators, including PGE2, ET1, Ang II, natriuretic peptides (ANP, BNP, and CNP), and nitric oxide synthases (iNOS, nNOS, and eNOS). Importantly, among these modulators, only BNP and iNOS were significantly reduced by rotenone treatment. Collectively, these findings demonstrated a substantial role of mitochondrial dysfunction in mediating the downregulation of NKCC2 and ENaCα in obstructive kidney disease, possibly via iNOS-derived nitric oxide and BNP.

Topics: Angiotensin II; Animals; Dinoprostone; Electron Transport Complex I; Epithelial Sodium Channels; Gene Expression Regulation; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Mitochondria; Natriuretic Peptide, Brain; Nitric Oxide; Nitric Oxide Synthase Type II; Rotenone; Signal Transduction; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Sodium-Potassium-Exchanging ATPase; Solute Carrier Family 12, Member 1; Solute Carrier Family 12, Member 3; Ureteral Obstruction

The present study was aimed at investigating whether the regulation of the local natriuretic peptide system is altered in the kidney and the vasculature in obstructive uropathy. Male Sprague-Dawley rats were bilaterally obstructed by ligation of the proximal ureters for 48 h. Control rats were treated in the same way, except that no ligature was made. The mRNA expression of the various isoforms of atrial, brain, and C-type natriuretic peptide (ANP, BNP, CNP) and different subtypes of natriuretic peptide receptor-A, -B, and -C (NPR-A, NPR-B, NPR-C) was determined in the kidney and the thoracic aorta by reverse transcription-polymerase chain reaction. The basal and stimulated activities of particulate guanylyl cyclase were also examined. Following the bilateral ureteral obstruction, the expression of ANP, BNP, and CNP was increased in the aorta as well as in the kidney. Contrary to this, the expression of NPR-A, NPR-B, and NPR-C was decreased both in the kidney and the aorta. Accordingly, the guanylyl cyclase activity was significantly decreased in response to natriuretic peptides. ANP relaxed phenylephrine-precontracted aortic rings in a dose-dependent manner, the degree of which was significantly diminished. Our results suggest that the local synthesis of natriuretic peptides is increased in the kidney and in the vasculature in obstructive uropathy.

Topics: Animals; Aorta, Thoracic; Atrial Natriuretic Factor; Blood; Guanylate Cyclase; Kidney; Male; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Ureteral Obstruction; Vasoconstriction