Table 2.
Experimental and clinical models of the PRR in glucose and lipid metabolism
| Experimental studies | Species | Model studied | Phenotypic characteristics | Organ specific effects | Reference |
|---|---|---|---|---|---|
| Handle region peptide (HRP) from 4 weeks to 28 weeks of age (0.1 mg/kg) | Rat | STZ induced Type 1 diabetes | No change in body weight or hyperglycemia | ↓ proteinuria and development of diabetic nephropathy | 5 |
| HRP from 4 weeks to 16 weeks of age (1mg/kg/day) | Mice | db/db mice | No change in body weight or hyperglycemia | ↓ proteinuria and development of diabetic nephropathy | 81 |
| HRP (0.1 mg/kg) or Imidapril (0.015% in water) from 8 weeks to 24 weeks of age | Mice | STZ induced Type 1 diabetes in AT1-receptor KO mice | No change in body weight or hyperglycemia but BP lower in ATKO mice and after Imidapril treatment | HRP prevented proteinuria and development of diabetic nephropathy while Imidapril ↓ proteinuria | 82 |
| HRP (0.2 mg/kg) or Valsartan (2 mg/kg/day) or both for 2 weeks | Rats | STZ induced Type 1 diabetes | No change in body weight, kidney weight or hyperglycemia | Both treatments ↓ proteinuria & inflammatory cytokines | 83 |
| HRP (0.1 mg/kg) or Imidapril (0.015% in water) from 17 weeks to 29 weeks of age | Rats | STZ induced Type 1 diabetes | No change in body weight or hyperglycemia but BP lower after Imidapril treatment | HRP reverses diabetic glomerulosclerosis while Imidapril ↓ renal further damage | 86 |
| HRP (0.1 mg/kg/day) for 10 weeks | Mice | High fat diet | HRP ↓ weight gain, plasma glucose, insulin and triglyceride levels | ↓ plasma and adipocyte leptin levels and adipocyte inflammatory markers | 64 |
| HRP (1mg/kg/day) or Aliskiren (10mg/kg/day) or combined treatment for 3 weeks | Rats | STZ induced Type 1 diabetes in heterozygousRen2 rats | Aliskiren alone decreased BP | Aliskiren alone ↓ proteinuria and glomerulosclerosis while HRP counteracts the effects of Aliskiren | 23 |
| HRP (1mg/kg/day) or Aliskiren (10mg/kg/day) or combined treatment for 3 weeks | Rats | STZ induced Type 1 diabetes in heterozygousRen2 rats | No change in blood glucose but BP lower in HRP and Aliskiren treatments | Aliskiren alone improved vascular dysfunction in diabetic rats and addition of HRP diminished the effects | 87 |
| HRP (0.1 mg/kg/day) or Imidapril (0.015% or 0.060% in water) or combined treatment for 4 weeks | Rats | STZ induced Type 1 diabetes stroke prone SHR | HRP had no effect on BP while Imidapril & combined treatment lowered BP, no change in blood glucose | Combined treatment ↓ cardiac weight, proteinuria & glomerulosclerosis than HRP or Imidapril alone | 85 |
| HRP (0.1 mg/kg/day) or Quinapril (50 mg/kg/day) or combined treatment for 8 weeks | Rats | STZ induced Type 1 diabetes | No change in blood glucose or body weight, blood pressure not measured | Combined treatment and Quinapril ↓ proteinuria and tubular injury but not HRP;HRP & Quinapril ↓ glomerular but no additive effects | 84 |
| Ceacam1 KO mice (model of insulin resistance) | Mice | Normal fat diet | ↑ blood pressure | ↑ expression of medullary PRR and activation of tubular RAS components | 93 |
| Ceacam1 KO mice (model of insulin resistance) | Mice | High fat diet for 8 weeks | Visceral obesity and postprandial hyperglycemia | ↑ expression of medullary PRR and activation of tubular RAS components | 94 |
| Renal tubule PRR KO | Mice | High fat diet for 10 weeks | ↓ obesity induced hypertension | ↓ α ENaC abundance in the kidney | 95 |
| Adipocyte PRR KO (Adiponectin-Cre) | Mice | High fat diet for 16 weeks | Prevented development of obesity | ↑ plasma insulin levels and improved insulin sensitivity | 21 |
| Adipocyte PRR KO (Adipocyte protein 2-Cre) | Mice | High fat diet for 9 weeks | ↓ weight gain, ↑ basal metabolic rate | ↑ plasma insulin and adiponectin levels and improved insulin sensitivity | 22 |
| Antisense oligonucleotide to block hepatic PRR | Mice | Normal or high fat diet | ↓ diet induced obesity and hepatosteatosis | ↑ plasma LDL levels, ↑ triglyceride levels | 99 |
| Adeno-Cre injection to reduce liver PRR | Mice | Floxed PRR mice | ↑ plasma cholesterol | ↑ liver injury and autophagy defects | 100 |
| Clinical studies | Species | Mutations | Predominant characteristics | Other features | |
| Missense mutations in PRR (N=3) | Human | c.293T>C c.212G>A |
Liver cirrhosis and immunodeficiency | Intellectual disability, ataxia, and cutis laxa | 100,101 |
STZ - streptozotocin; ENaC – epithelial Na channel; RAS – renin angiotensin system blocker; AT1 – angiotensin-II Type 1 receptor; LDL- low density lipoprotein