MicroRNAs as potential therapeutic targets in kidney disease

Abstract

One cornerstone of chronic kidney disease (CKD) is fibrosis, as kidneys are susceptible due to their high vascularity and predisposition to ischemia. Presently, only therapies targeting the angiotensin receptor are used in clinical practice to retard the progression of CKD. Thus, there is a pressing need for new therapies designed to treat the damaged kidney. Several independent laboratories have identified a number of microRNAs that are dysregulated in human and animal models of CKD. This review will explore the evidence suggesting that by blocking the activity of such dysregulated microRNAs, new therapeutics could be developed to treat the progression of CKD.

Figure 1. Characteristics of chronic kidney disease in glomeruli and interstitium of kidney cortex

(A) Normal human glomerulus and surrounding tubules and peritubular capillaries (PTCs) filled with erythrocytes (* placed above examples of PTCs) stained with Silver methenamine combined with PAS (Jones) stain which highlights collagens. Arteriole (a) is shown. Note back-to-back tubules with cuboidal or columnar epithelium. (B) Sclerotic glomerulus showing wedge shaped sclerotic region showing dense pink material on PAS stained section (arrowhead) and rather acellular weaker pink stained material more peripherally (arrow) and obliteration of capillary loops. Sclerotic region is fused to Bowman’s capsule where there is local destruction of the basement membrane and periglomerular fibrosis (thick arrow). At the lower pole, a combination of increased cellularity and fibrosis in the mesangium, and basement membrane thickening in glomerular loops. (C) Jones stained image of cortex from diabetic nephropathy, showing injured tubules (tubule atrophy and tubule cell vacuolization, apoptotic cells, arrow), marked reduction in capillary density (* placed adjacent to examples of PTCs), expansion of the interstitial space with fibrotic material (fine black stain), and an increase in inflammatory cells. Note also thickening of the tubule basement membrane (black). (D) Trichrome stained image of kidney cortex from ischemic kidney disease showing marked expansion of interstitial fibrosis (cyan color), which has overtaken all of the tubules. The fibrosis is cellular showing inflammatory cells and myofibroblasts. The remaining tubules all show tubular atrophy with intraluminal debris. (E) Schema showing cellular mechanisms of CKD development in the kidney cortical interstitium.

Figure 2. Kidney disease in mice that lack miR-21 compared to WT mice following kidney injury

Sirius red stained low power images showing red stained interstitial fibrosis following kidney injury, and medium power images showing PAS stain of kidney cortex after injury. Note reduced fibrosis in kidneys lacking miR-21. Also note that kidney epithelial cells are more injured in WT showing increased flattening and loss of typical purple brush border, whereas these features are more preserved in miR21^−/− kidneys.

Figure 3. Schema showing importnat gene products and pathways silenced by miR-21 in animal models of kidney disease

MiR-21 silences the transcriptional regulator PPARα and many of the downstream enzymes in fatty acid metabolism that are also regulated by PPARα, including transporters and enzymes (shown in grey) of the β-oxidation metabolic pathway of fatty acids that occurs in peroxisomes and mitochondria. The consequence of miR-21 activity is to reduce metabolism of fatty acids. In addition, miR-21 increases reactive oxygen species and toxin formation/accumulation. First, by suppressing peroxisome formation and activity, the metabolism of H₂O₂ is retarded by miR-21, and second, miR-21 silences genes that inhibit ROS generation in mitochondria, including MPV17-like which exerts its inhibitory function by binding to the mitochondrial protease HrtA2. In this configuration HrtA2 is also anti-apoptotic.