Protein kinase C inhibitor prevents renal apoptotic and fibrotic changes in response to partial ureteric obstruction

Abstract

What ' s known on the subject? and What does the study add? Protein kinase C inhibitor (PKCI) can decrease glomerular and tubular cell apoptosis and mitosis and attenuate collagen accumulation and fi bronectin expression in a PUUO rat model.Although the role of PKC has been well studied in diabetic nephropathy, there is no report on its role in obstructive nephropathy. This investigation evaluated the processes that were associated with the activation of PKC α and PKC β pathways and showed that PKCI played an important role in the protection of renal function during ureteric obstruction. OBJECTIVES• To investigate the expression of the protein kinase C (PKC) pathway after partial unilateral ureteric obstruction (PUUO).• To evaluate the therapeutic potential of a PKC inhibitor (PKCI) in obstructive nephropathy. MATERIALS AND METHODS• Thirty-six rats were divided into three groups. One sham-operated group served as the control. The other two groups received PUUO surgery, after which one group received no treatment and the other group was treated with PKCI, chelerythrine.• The severity of hydronephrosis and renal morphology were assessed: tubular and glomerularcell apoptosis, mitosis and interstitial fi brosis were examined using immunohistochemistry.• Western immunoblots were performed to determine fi bronectin, transforming growth factor-β (TGF-β ), and PKC isoform levels. RESULTS• Two weeks after PUUO surgery, hydronephrosis progressively developed. Tubular-interstitial fi brosis, collagen deposition and fi bronectin expression were increased.• PUUO also activated the expression of PKC α and PKC β and the translocation of PKCs from cell cytosol to cell membranes.• Treatment with PKCI signifi cantly decreased PKC α and PKC β expression and translocation in the renal cortex.• Treatment with PKCI also reduced the severity of hydronephrosis, decreased both glomerular and tubular cell apoptosis and mitosis, and attenuated the collagen and fi bronectin accumulation in renal interstitium. CONCLUSIONS• Renal tubular apoptosis and interstitial fi brosis after obstructive nephropathy are associated with PKC α and PKC β activation.• The PKCI, chelerythrine, is capable of decreasing PKC expression and translocation in the renal cortex, suggesting that this inhibitor may have therapeutic potential in the protection of renal function in the fi rst few weeks after PUUO surgery.

A Glimpse of the Mechanisms Related to Renal Fibrosis in Diabetic Nephropathy

“…PKC belongs to multi-functional serine and threonine kinase and is widely distributed in the body, which plays a key role in glucose metabolism, cell differentiation, gene expression regulation, and inflammatory process (Juan et al 2012). It can be divided into 3 categories and 12 subtypes: traditional PKCs (PKC-α/β1/β2/γ), which can be activated by both Ca 2+ and diacylglycerol (DAG); new PKCs (PKC-δ/ε/θ/μ/η), which can be activated by DAG; atypical PKCs (PKC-λ/ζ), which are activated by neither Ca 2+ nor DAG (Zhang et al 2014).…”

Eugenol ameliorates renal damage in streptozotocin‐induced diabetic rats

“…There are three major mechanisms and elevated blood glucose level is the central driving force to initiate them. Abnormality of intracellular signalling and metabolism is first mechanism, which involves activation of polyol pathway, protein kinase C pathway and hexosamine pathway . Another mechanism is the generation of free radicals leading to increased oxidative stress and formation of advanced glycation end products (AGEs) .…”

An extract of Pueraria tuberosa tubers attenuates diabetic nephropathy by upregulating matrix metalloproteinase‐9 expression in the kidney of diabetic rats

“…where Nx is the number of glomeruli with a particular score [1][2][3][4] for a given section. 37 To determine the EC index (ECI), H&E-stained sections were examined at a magnification of ×400, with 1000 tubules randomly counted per section in 50 fields.…”

“…Management of later stages of CKD is expensive, placing a considerable financial burden on society. The pathogenesis of CKD is known to include deregulation of the polyol pathway, the formation and accumulation of advanced glycation end‐products (AGEs), the hexosamine pathway, which is responsible for the excess glycation of proteins, the activation of protein kinase C (PKC), growth factors, cytokines, poly(ADP‐ribose) polymerase (PARP), and mitogen‐activated protein kinase (MAPK), and the accumulation of free radicals . However, currently there is no drug available that can treat DN, with only hypoglycemic and antihypertensive drugs in clinical use.…”