Renal ROCK Activation and Its Pharmacological Inhibition in Patients With Diabetes

Keiichiro Matoba,Kensuke Sekiguchi,Hiroshi Takahashi,Kazunori Utsunomiya,Yusuke Takeda,Yosuke Nagai,Tamotsu Yokota,Rimei Nishimura

doi:10.3389/fphar.2021.738121

Abstract

Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine/threonine kinase with essential roles in cytoskeletal functions. Substantial evidence implicates ROCK as a critical regulator in the inception and progression of diabetic nephropathy through a mechanism involving mesangial fibrosis, podocyte apoptosis, and endothelial inflammation. Despite these experimental observations, human data is lacking. Here we show that the phosphorylated form of myosin phosphatase targeting subunit 1 (MYPT1), a ROCK substrate, was increased in both the glomerular and tubulointerstitial areas in patients with histologically confirmed diabetic nephropathy. We also conducted a retrospective pilot analysis of data from patients with diabetes to assess the renoprotective effects of fasudil, an ATP-competitive ROCK inhibitor licensed in Japan for the prevention of vasospasm following subarachnoid hemorrhage. Fifteen subjects (male, n = 8; female, n = 7; age 65.7 ± 14.7 years; body height, 161.1 ± 12.6 cm; body weight, 57.6 ± 13.7 kg; body mass index, 22.4 ± 3.7 kg/m2) were enrolled to evaluate blood pressure and the renal outcome after fasudil treatment. Of note, proteinuria was significantly reduced at the end of the fasudil treatment without affecting the blood pressure or estimated glomerular filtration rate. Taken together, these findings suggest that the administration of fasudil could be associated with a better renal outcome by inhibiting the ROCK activity in patients with diabetes.

Highlights

Diabetic nephropathy is a major health concern that imposes a significant risk for end-stage renal disease
The progression of diabetic nephropathy is still associated with high mortality and morbidity rates, Renal Rho-associated coiled-coil-containing protein kinase (ROCK) Activation in Diabetes even when patients receive the current standard of care
Renal ROCK Activity is Elevated in Patients With Diabetic Nephropathy

Summary

Introduction

Diabetic nephropathy is a major health concern that imposes a significant risk for end-stage renal disease. A series of clinical trials demonstrated significant improvement in renal outcomes of patients with diabetic nephropathy after long-term treatment with sodium glucose co-transporter 2 inhibitors (Wanner et al, 2016), mineralocorticoid receptor antagonists (Lytvyn et al, 2019), endothelin receptor antagonists (Cahn et al, 2019), or Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors (Brosius et al, 2016). Experimental studies have demonstrated that the phosphorylated form of MYPT1 is increased in the renal cortex of both type 1 and type 2 diabetes rodent models (Peng et al, 2008; Matoba et al, 2013), indicating that ROCK activity is enhanced in the diabetic kidney, regardless of the type of diabetes. ROCK plays a key role in the process of vascular smooth muscle contraction and the pathogenesis of vascular spasm (Masumoto et al, 2002; Wickman et al, 2003)

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