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Author Spotlight: Network Pharmacology and Molecular Docking to Decipher the Action of Jiawei Shengjiang San Against Diabetic Kidney Disease
Published on: May 10, 2024
Harnessing ROCK biology to revolutionize diabetic nephropathy: decoding mechanisms, designing therapies
1Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishishimbashi, Minato-ku, Tokyo, 105-8461 Japan.
Abstract:
Diabetes remains a major cause of kidney failure globally, presenting substantial challenges to healthcare systems worldwide. Although significant progress has been made in understanding its pathogenesis, residual risks persist despite current therapies. Emerging evidence underscores the pivotal role of small GTPases-particularly Rho and Rho-associated coiled-coil-containing protein kinase (ROCK)-in the progression of diabetic nephropathy. This comprehensive review consolidates current knowledge on the distinct pathophysiological roles of the ROCK isoforms, ROCK1 and ROCK2, in diabetic nephropathy, drawing on recent insights from both genetic and pharmacological studies. We explore how ROCK signaling interfaces with key pathological mechanisms, including podocyte injury, glomerulosclerosis, tubular dysfunction, and metabolic disturbances. Particular emphasis is placed on isoform-specific functions: ROCK1 primarily regulates AMP-activated protein kinase-mediated fatty acid metabolism and mitochondrial dynamics, while ROCK2 modulates peroxisome proliferator-activated receptor α signaling and inflammatory responses. Furthermore, we discuss the translational implications of these findings, focusing on the therapeutic potential of ROCK inhibitors in chronic kidney disease (CKD) with diabetes and related disorders, such as focal segmental glomerulosclerosis, as well as their impact on electrolyte balance. By integrating molecular insights with clinical considerations, this review provides a framework for developing targeted strategies to halt the CKD progression in people with diabetes.
Insights
Small GTPases, specifically Rho-associated coiled-coil-containing protein kinase (ROCK) isoforms ROCK1 and ROCK2, are key drivers of diabetic kidney disease. Targeting ROCK signaling offers a promising therapeutic strategy for halting chronic kidney disease progression in diabetic patients.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Diabetic nephropathy is a leading cause of kidney failure worldwide.
- Current therapies leave residual risks, highlighting the need for novel treatment strategies.
- Small GTPases, particularly Rho-associated coiled-coil-containing protein kinase (ROCK) signaling, are implicated in diabetic kidney disease progression.
Purpose of the Study:
- To review the distinct pathophysiological roles of ROCK1 and ROCK2 isoforms in diabetic nephropathy.
- To explore the molecular mechanisms by which ROCK signaling contributes to kidney damage.
- To discuss the therapeutic potential of ROCK inhibitors for diabetic kidney disease and related disorders.
Main Methods:
- Comprehensive literature review of genetic and pharmacological studies.
- Analysis of ROCK isoform-specific functions in key pathological pathways.
- Integration of molecular insights with clinical implications for chronic kidney disease (CKD) management.
Main Results:
- ROCK1 regulates AMP-activated protein kinase-mediated fatty acid metabolism and mitochondrial dynamics.
- ROCK2 modulates peroxisome proliferator-activated receptor α signaling and inflammatory responses.
- ROCK signaling contributes to podocyte injury, glomerulosclerosis, tubular dysfunction, and metabolic disturbances.
Conclusions:
- ROCK1 and ROCK2 play distinct, critical roles in the pathogenesis of diabetic nephropathy.
- Targeting ROCK signaling, via ROCK inhibitors, presents a viable therapeutic avenue for diabetic kidney disease.
- Further research into isoform-specific inhibition could lead to more effective treatments for CKD in diabetic patients.
