Renal ROCK Activation and Its Pharmacological Inhibition in Patients With Diabetes

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.

Sitagliptin Mitigates Diabetic Nephropathy in a Rat Model of Streptozotocin-Induced Type 2 Diabetes: Possible Role of PTP1B/JAK-STAT Pathway

“…The only currently approved treatment for DN is the blockade of the renin–angiotensin system (RAS), which appeared to be effective 20 years ago. However, this treatment has various limitations and does not result in significant benefits for patients with DN [ 26 , 27 ]. Therefore, identifying potential new therapies and molecular targets is of immense practical importance.…”

Kidney microRNA Expression Pattern in Type 2 Diabetic Nephropathy in BTBR Ob/Ob Mice

“…Apart from these mentioned drugs, the dipeptidyl peptidase 4 inhibitors are also a therapeutic approach currently recommended in the new KDIGO guidelines ( Kidney Disease: Improving Global Outcomes Diabetes Work Group, 2020 ). In addition, new anti-inflammatory therapies and metabolic modulators, such as JAK/STAT, Rho-kinase and Sirtuin-3 inhibitors, peptide N-Acetyl-Seryl-Aspartyl-Proline, glycolysis inhibitors, and mineralocorticoid receptor antagonists, have been postulated as potential drugs in DN due to the preclinical evidence, showing their renoprotective role or even their ability to reverse established renal damage ( Hashimoto et al, 2010 ; Bakris et al, 2020 ; Locatelli et al, 2020 ; Opazo-Ríos et al, 2020b ; Srivastava et al, 2020 ; Matoba et al, 2021 ). Growing evidence in all these mentioned studies has shown that the reno-protective effects of these drugs, at least, in part, may be due to the regulation of epithelial and endothelial-to-mesenchymal transition (EMT and EndoMT) in the progression of DN.…”

NLRP3-mediated pyroptosis in diabetic nephropathy

“…Fasudil also ameliorated albuminuria and glomerular hypertrophy in DN mice by downregulating HIF-1α expression ( Matoba et al, 2013 ). Furthermore, the application of fasudil can reduce proteinuria and improve renal prognosis by inhibiting ROCK activity in diabetic patients ( Matoba et al, 2021 ). Studies have also shown that fasudil can inhibit NF-κB nuclear translocation and TGF-β1 expression in STZ-induced diabetic rats ( Xie et al, 2013 ).…”