Mineralocorticoid Receptor-Associated Mechanisms in Diabetic Kidney Disease and Clinical Significance of Mineralocorticoid Receptor Antagonists

Abstract

Background: Diabetic kidney disease (DKD) is a common disorder with multiple serious clinical implications, including an increased risk of end-stage kidney disease (ESKD), cardiovascular complications, heart failure, onset or worsening of hypertension, and premature death. Patients with DKD frequently require dialysis or kidney transplantation to manage their ESKD. Summary: Upregulation of the renin–angiotensin–aldosterone system is an important contributor to kidney disease progression, as highlighted by the results of trials evaluating angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with albuminuria. Increasing evidence suggests the existence of a multidirectional network that involves aldosterone, the mineralocorticoid receptor (MR), and the Ras-related C3 botulinum toxin substrate 1 (Rac1) as driving forces in the generation of reactive oxygen species and oxidative stress-induced injury in the initiation of interstitial nephritis and eventual fibrosis in chronic kidney disease and DKD. The MR is a key element of this triangle, as highlighted by the beneficial effect of MR antagonists in preventing or reducing aldosterone- or Rac1-related effects in basic science studies, and the improved patient outcomes observed in clinical studies. Key Messages: Aldosterone can promote kidney disease in diabetes via the MR and via MR-independent actions through Rac1. However, the MR remains a key element of this triangle, with clinical data supporting the use of MR antagonists in delaying the progression of kidney disease in diabetes.

Pathomechanisms of Diabetic Kidney Disease

“…While it is acknowledged that aldosterone exhibits MR-independent effects contributing to DKD development, and Rac1 can be upregulated without MR activation, MR remains a pivotal component in this interaction. Clinical evidence supports the efficacy of the novel non-steroidal MR antagonist (nsMRA), finerenone, in slowing the progression of DKD [256].…”

“…There is growing evidence indicating the existence of an intricate network involving aldosterone, the MR, and Ras-related C3 botulinum toxin substrate 1 (Rac1) as crucial elements in the generation of ROS and subsequent damage caused by oxidative stress. This dynamic interaction plays a significant role in initiating interstitial nephritis, ultimately culminating in fibrosis in cases of DKD [256].…”

“…stress. This dynamic interaction plays a significant role in initiating interstitial nephritis, ultimately culminating in fibrosis in cases of DKD [256].…”

Finerenone: From the Mechanism of Action to Clinical Use in Kidney Disease

“…It is initiated by epithelial trauma (due to toxins), inflammation, or direct tubular injury, as observed with albuminuria in diabetes [ 23 ]. Increasing evidence suggests that the upregulation of aldosterone is pivotal in progressive fibrosis, CKD, and DKD [ 24 ]. Increased renin production causes an increase in angiotensin II, which leads to an increase in aldosterone production through the upregulation of aldosterone synthase.…”

Overview of the safety, efficiency, and potential mechanisms of finerenone for diabetic kidney diseases

“…Nevertheless, a greater treatment effect was noted on the eGFR ≥57% kidney composite endpoint, with a 36% relative risk reduction for ESKD (P = 0.041) ( 87 ). FIN achieved a 32% greater reduction in UACR from baseline to 4 months compared to placebo ( 87 ), and its impact on kidney outcomes was particularly pronounced in patients with significantly elevated albuminuria as opposed to those with moderately increased albuminuria ( 97 ). An analysis derived from the FIGARO-DKD study emphasizes the importance of albuminuria screening in T2D patients, as early initiation of treatment effectively mitigated the risk of CV events and albuminuria progression in individuals with moderately elevated albuminuria ( 98 ).…”