Testosterone enhances tubuloglomerular feedback by increasing superoxide production in the macula densa

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 304; no. 9; pp. R726 - R733
• Main Authors: Fu, Yiling, Lu, Yan, Liu, Eddie Y, Zhu, Xiaolong, Mahajan, Gouri J, Lu, Deyin, Roman, Richard J, Liu, Ruisheng
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2013
• Subjects: Androgen Antagonists - pharmacology; Animals; Cardiovascular and Renal Integration; Cell Line; Cells; Cyclic N-Oxides - pharmacology; Cyclooxygenase 2 Inhibitors - pharmacology; Feedback, Physiological - drug effects; Fluid and Electrolyte Homeostasis; Flutamide - pharmacology; Free Radical Scavengers - pharmacology; Gender differences; Hypertension; Kidney diseases; Kidney Glomerulus - drug effects; Kidney Tubules - drug effects; Male; NADPH Oxidases - metabolism; Nitrobenzenes - pharmacology; Polyethylene glycol; Rats; Rats, Sprague-Dawley; Receptors, Androgen - drug effects; RNA - biosynthesis; RNA - genetics; Rodents; Spin Labels; Sulfonamides - pharmacology; Superoxide Dismutase - pharmacology; Superoxides - metabolism; Testosterone; Testosterone - pharmacology; Xanthine Oxidase - metabolism; testosterone; superoxide; tubuloglomerular feedback
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00341.2012

Males have higher prevalence of hypertension and renal injury than females, which may be attributed in part to androgen-mediated effects on renal hemodynamics. Tubuloglomerular feedback (TGF) is an important mechanism in control of renal microcirculation. The present study examines the role of testosterone in the regulation of TGF responses. TGF was measured by micropuncture (change of stop-flow pressure, ΔPsf) in castrated Sprague-Dawley rats. The addition of testosterone (10(-7) mol/l) into the lumen increased the ΔPsf from 10.1 ± 1.2 to 12.2 ± 1.2 mmHg. To determine whether androgen receptors (AR) are involved, mRNA of AR was measured in the macula dense cells isolated by laser capture microdissection from kidneys, and a macula densa-like cell line (MMDD1). AR mRNA was expressed in the macula densa of rats and in MMDD1 cells. We next examined the effects of the AR blocker, flutamide (10(-5) mol/l) on the TGF response. The addition of flutamide blocked the effects of testosterone on TGF. The addition of Tempol (10(-4) mol/l) or polyethylene glycol-superoxide dismutase (100 U/ml) to scavenge superoxide blocked the effect of testosterone to augment TGF. We then applied apocynin to inhibit NAD(P)H oxidase and oxypurinol to inhibit xanthine oxidase and found the testosterone-induced augmentation of TGF was blocked. In additional experiments in MMDD1 cells, we found that testosterone increased O2(-) generation. Apocynin or oxypurinol blocked the testosterone-induced increases of O2(-), while blockade of COX-2 with NS-398 had no effect. These findings suggest that testosterone enhances TGF response by stimulating O2(-) production in macula densa via an AR-dependent pathway.