Reduced Levels of Cyclic-GMP and Inhibition of cGMP-Dependent Protein Kinase Activate p21<sup>Cip1</sup>/p27<sup>Kip1</sup> and Lead to Renal Fibrosis and Dysfunction
October 22, 2020 | 10:00 AM - 12:00 PM
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Reduced Levels of Cyclic-GMP and Inhibition of cGMP-Dependent Protein Kinase Activate p21Cip1/p27Kip1 and Lead to Renal Fibrosis and Dysfunction
- AKI Mechanisms - 3
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Das, Subhankar, Tulane University Health Sciences Center School of Medicine, New Orleans, Louisiana, United States
- Neelamegam, Kandasamy, Tulane University Health Sciences Center School of Medicine, New Orleans, Louisiana, United States
- Pandey, Kailash Nath, Tulane University Health Sciences Center School of Medicine, New Orleans, Louisiana, United States
Kailash Nath Pandey,
Targeted-deletion of Npr1 (coding for guanylyl cyclase/natriuretic peptide receptor-A, GC-A/NPRA) exhibits hypertrophic and proliferative effects in target organs of Npr1 gene-knockout mice; however, the molecular mechanisms of these pathologies are poorly understood. Fibrosis and hypertrophy are regulated by p21Cip1 and p27Kip1, cell-cycle regulatory proteins that inhibit cyclin and cyclin-dependent kinase (cyclin-CDK) complex.
We examined the activation of CDK blocker (p21Cip1/p27Kip1) in Npr1 gene-knockout (0-copy; Npr1-/-) mice and the GC inhibitor, A71915-treated and cGMP-dependent protein kinase (cGK) inhibitor, Rp-8-Br-cGMPS (Rp)-treated wild-type 2-copy (Npr1+/+) and gene-duplicated 4-copy (Npr1++/++) mice using Western blot and quantitative real-time PCR. Systolic blood pressure (BP) was determined by non-invasive tail-cuff method.
Renal cGMP levels and cGK activity were significantly decreased in 0-copy mice (p<0.0001), A71915-treated (p<0.001) and Rp-treated (p<0.05) 2-copy and 4-copy mice as compared with control animals. The results showed a high BP level in 0-copy mice (138.6 ± 3.1 mmHg; p<0.001) and significantly lower BP in 4-copy mice (86.0 ± 2.8 mmHg; p<0.01) compared to 2-copy mice (102.2 ± 1.7 mmHg). Treatment with A71915 and Rp showed significant increase in BP in 2-copy mice but only a small increase in 4-copy mice compared with untreated control animals. Increased phosphorylation of p-Erk1/2 (3-fold), p-p38MAPK (4-fold), p21Cip1 (6-fold), and p27Kip1 (5-fold) occurred in 0-copy, A71915-treated 2-copy, and A71915-treated 4-copy mice; however, Rp treatment caused minimal changes compared to controls. Proinflammatory and profibrotic cytokines, including TNF-α (6-fold), IL-6 (3-fold), and TGF-β1 (4-fold) were increased in plasma and kidney of 0-copy and A791915-treated 2-copy mice, but less in A71915-treated 4-copy mice. Renal pathology, including fibrosis, mesangial matrix expansion, and tubular hypertrophy were significantly higher in 0-copy and A71915-treated 2-copy mice but minimally in 4-copy mice compared with controls.
The present results suggest that Npr1 has a pivotal role in inhibiting the renal fibrosis and pathology and exerts renal protective effects through the cGMP/cGK axis by repressing the CDK inhibitors, p21Cip1 and p27Kip1.
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