Targeting of RhoA/ROCK Signaling Ameliorates Progression of Diabetic Nephropathy Independent of Glucose Control
Vasantha Kolavennu 1 ,
Lixia Zeng 1 ,
Hui Peng 1 ,
Yin Wang 2 and
Farhad R. Danesh 2
1 Department of Medicine, Feinberg School of Medicine, Northwestern University, Houston, Texas
2 Department of Medicine, Nephrology Section, Baylor College of Medicine, Houston, Texas
Address correspondence and reprint requests to Farhad R. Danesh, MD, Division of Nephrology, Baylor College of Medicine, One
Baylor Plaza, Alkek N-520, Houston, TX 77030-3411. E-mail: danesh{at}bcm.edu
Abstract
OBJECTIVE— RhoA, a small GTPase protein, and its immediate downstream target, Rho kinase (ROCK), control a wide variety of signal transduction
pathways. Recent studies have shown that fasudil, a selective ROCK inhibitor, may play a pivotal role in a number of pathological
conditions, ranging from cardiovascular diseases to pulmonary hypertension and erectile dysfunction. Considerable evidence
suggests that some of the beneficial effects of statins may also stem from their modulatory effects on RhoA/ROCK signaling.
In the current study, we hypothesized that pharmacological blockade of the RhoA/ROCK pathway with either fasudil or simvastatin
would ameliorate progression of diabetic nephropathy.
RESEARCH DESIGN AND METHODS— In two separate experiments, diabetic db/db mice received fasudil (10 mg · kg − · day − i.p.) or simvastatin (40 mg · kg − · day − p.o.) for 16 weeks. Untreated db/db and db/m mice served as controls.
RESULTS— The kidney cortices of untreated db/db mice displayed increased ROCK activity compared with db/m mice. The fasudil-treated mice exhibited a significant reduction
in ROCK activity, albuminuria, glomerular collagen IV accumulation, and urinary collagen IV excretion compared with untreated
db/db mice. Interestingly, blood glucose was unaffected by fasudil administration. Treatment with simvastatin significantly attenuated
RhoA activation in the kidney cortices of db/db mice and resulted in a significant reduction of albuminuria and mesangial matrix expansion.
CONCLUSIONS— Based on these results, we propose that RhoA/ROCK blockade constitutes a novel approach to the treatment of diabetic nephropathy.
Our data also suggest a critical role for RhoA/ROCK activation in the pathogenesis of diabetic nephropathy.
GBM, glomerular basement membrane
MMI, mesangial matrix index
MYPT1, myosin phosphatase target subunit 1
PAS, periodic acid-Schiff
ROCK, Rho kinase
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 14 December 2007. DOI: 10.2337/db07-1241.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
See accompanying commentary, p. 532.
Received September 1, 2...

Targeting of RhoA/ROCK Signaling Ameliorates Progression of Diabetic Nephropathy Independent of Glucose Control

10.2337/db07-1241