PT  - JOURNAL ARTICLE
AU  - Shohei Oishi
AU  - Naoko Suzuki
AU  - Yuri Hasui
AU  - Tsuyoshi Homma
AU  - Masanori Obana
AU  - Takahiro Nagayama
AU  - Yasushi Fujio
TI  - Sustained activation of guanylate cyclase-A with TDT, a natriuretic peptide derivative, exhibits cardiorenal protection in Dahl salt-sensitive hypertensive rats
AID  - 10.1124/jpet.117.244459
DP  - 2017 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.117.244459
4099  - http://jpet.aspetjournals.org/content/early/2017/10/11/jpet.117.244459.short
4100  - http://jpet.aspetjournals.org/content/early/2017/10/11/jpet.117.244459.full
AB  - Heart failure often presents with prognosis-relevant impaired renal function. To investigate whether the chronic activation of guanylate cyclase-A (GC-A) protects both heart and kidney, we examined the effects of TDT, a neprilysin (NEP)-resistant natriuretic peptide (NP) derivative, on cardiac and renal dysfunction in Dahl salt-sensitive hypertensive rats (DS rats). Pretreatment with NEP or NEP inhibitor did not influence GC-A activation by TDT both in vitro and in vivo, resulting in a long-acting profile of TDT compared to native human atrial NP (hANP). The repeated administration of TDT to DS rats suppressed the progress of cardiac hypertrophy, systolic/diastolic dysfunction, and proteinuria in a dose-dependent manner without influencing blood pressure. Compared with vehicle and hANP, salt diet-induced podocyte injury was reduced by TDT, analyzed by urinary podocalyxin concentration, renal expression of nephrin mRNA, and glomerular expression of desmin protein. Since glomerular TRPC6 plays detrimental roles in podocyte homeostasis, we examined the renal expression of TRPC6 in DS rats and found that salt diet upregulated the expression of TRPC6. Importantly, TRPC6 induction was significantly decreased in TDT treated rats, compared with vehicle and hANP. Consistently, in primary cultured podocytes from DS rats, TDT inhibited ATP-induced calcium influx, similar to TRPC inhibitor SKF96365. Finally, TDT-mediated protection of podocytes was abolished by PKG inhibitor KT5823. In conclusion, TDT treatment attenuated heart and kidney dysfunction, accompanied by podocyte protection through inhibition of TRPC6. Thus, long-acting NPs could be new avenues for treatment of heart failure.