Very high doses of valsartan provide renoprotection independently of blood pressure in a type 2 diabetic nephropathy rat model

Naoto Tominaga, Annie Robert, Yuko Izuhara, Shuichi Ohtomo, Takashi Dan, Kazuo Chihara, Kiyoshi Kurokawa, Charles Van Ypersele De Strihou, Toshio Miyata

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Aim:Angiotensin II type 1 receptor blockers (ARB) retard the progression of hypertensive diabetic kidney disease. Clinical evidence suggests that the dose of ARB required to correct hypertension is suboptimal for renoprotection evaluated by proteinuria. No systematic, prospective study has yet evaluated separately the effect of increasing doses of ARB on blood pressure and proteinuria. Methods: Over a period of 8 weeks, the effect of seven constant doses of an ARB, valsartan (4-160 mg/kg per day), on blood pressure and proteinuria taken as a surrogate marker of nephropathy in a hypertensive, type 2 diabetic rat model, the spontaneously hypertensive/NIH-corpulent rat (SHR/NDmcr-cp), was assessed. In this spontaneously hypertensive rat strain, a genetic mutation in the leptin receptor gene is associated with hyperphagia leading to obesity with metabolic syndrome and eventually to nephropathy. Results: No additional blood pressure lowering was observed above 120 mg/kg per day of valsartan, suggesting that a dose of 80-120 mg/kg per day had a maximal effect. Nevertheless, higher doses of valsartan further reduced proteinuria in a dose-dependent fashion suggesting the absence of a maximal dose. Obesity, hyperglycaemia and hypercholesterolaemia were unaffected but hypertriglyceridaemia was partially corrected at various ARB doses. Conclusion: ARB improve renoprotection at doses above those required for a maximal effect on blood pressure. The mechanism of the renoprotection obtained at high doses of ARB is yet to be elucidated.

Original languageEnglish
Pages (from-to)581-587
Number of pages7
JournalNephrology
Volume14
Issue number6
DOIs
Publication statusPublished - 2009 Sep

Keywords

  • Angiotensin II receptor type 1 blocker
  • Blood pressure
  • Optimal dose
  • Proteinuria
  • Renoprotection

ASJC Scopus subject areas

  • Nephrology

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