Diabetic nephropathy is the leading cause of ESRD, but its pathogenesis is controversial. The reason only some patients with IDDM or NIDDM develop overt nephropathy remains unknown. A large number of potential pathogenetic mechanisms postulated to cause or enhance renal damage, and shared with human diabetes, have been identified in rodent models. Nevertheless, IDDM models, including the widely used streptozotocin (STZ) induced diabetes model, are very resistant to the development of overt nephropathy. By contrast, some recently described NIDDM models do develop clinical and histologic nephropathy. The mechanisms critical to this differential susceptibility have not been defined. Using chronic BP radiotelemetry over 10 months, we have shown that partially-insulin treated STZ diabetes is associated with a significantly lower BP and postulated that such BP reductions may counteract the adverse effects of the other described pathogenetic mechanisms. We propose to test the hypothesis that the diabetic milieu although necessary, is not sufficient for the expression of the overt diabetic nephropathy and that an increased renal BP exposure is a necessary permissive factor.
Specific Aim 1 will test the hypothesis that enhanced renal BP exposure acts synergystically with the diabetic milieu in the pathogenesis of overt diabetic nephropathy. Chronic BP radiotelemetry and BP power spectral analysis will be used to quantitate the total BP load and its individual components in nephropathy susceptible models (OLETF, SHROB, SHR/N-cp, ZSF) and their control strains. Dynamic BP transmission to the renal microvasculature will be quantitatively assessed by (i) renal autoregulatory capacity in conscious rats using renal arterial flow probes, with methods for data acquisition and analysis that have recently been developed in our laboratory and (ii) by direct micropuncture measurements of glomerular pressure (PGC) in anesthetized rats. If the hypothesis is valid, the variable rate and severity of the development of overt nephropathy in these models will correlate with the parameters of renal BP exposure.
Specific Aim 2 will test the hypothesis that an enhanced renal BP exposure is necessary for the phenotypic expression of nephropathy in these models through pharmacologic reductions (antihypertensives) of specific components of the """"""""BP-load"""""""". These data will be compared to that separately being obtained in the STZ diabetes model in normotensive and hypertensive rat strains so as to define the differences between IDDM and NIDDM models. These novel investigations should provide valuable new insights into the role of BP mechanisms in the pathogenesis of the overt diabetic nephropathy phenotype.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cardiovascular and Renal Study Section (CVB)
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Meyers, Catherine M
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Loyola University Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Griffin, Karen A (2017) Hypertensive Kidney Injury and the Progression of Chronic Kidney Disease. Hypertension 70:687-694
Bidani, Anil K; Griffin, Karen A (2015) Basic science: hypertensive target organ damage. J Am Soc Hypertens 9:235-7; quiz 238
Polichnowski, Aaron J; Licea-Vargas, Hector; Picken, Maria et al. (2015) Glomerulosclerosis in the diet-induced obesity model correlates with sensitivity to nitric oxide inhibition but not glomerular hyperfiltration or hypertrophy. Am J Physiol Renal Physiol 309:F791-9
Polichnowski, Aaron J; Griffin, Karen A; Picken, Maria M et al. (2015) Hemodynamic basis for the limited renal injury in rats with angiotensin II-induced hypertension. Am J Physiol Renal Physiol 308:F252-60
Polichnowski, Aaron J; Lan, Rongpei; Geng, Hui et al. (2014) Severe renal mass reduction impairs recovery and promotes fibrosis after AKI. J Am Soc Nephrol 25:1496-507
Griffin, Karen A; Polichnowski, Aaron; Litbarg, Natalia et al. (2014) Critical blood pressure threshold dependence of hypertensive injury and repair in a malignant nephrosclerosis model. Hypertension 64:801-7
Polichnowski, Aaron J; Griffin, Karen A; Long, Jianrui et al. (2013) Blood pressure-renal blood flow relationships in conscious angiotensin II- and phenylephrine-infused rats. Am J Physiol Renal Physiol 305:F1074-84
Bidani, Anil K; Polichnowski, Aaron J; Loutzenhiser, Rodger et al. (2013) Renal microvascular dysfunction, hypertension and CKD progression. Curr Opin Nephrol Hypertens 22:1-9
Griffin, Karen; Polichnowski, Aaron; Licea-Vargas, Hector et al. (2012) Large BP-dependent and -independent differences in susceptibility to nephropathy after nitric oxide inhibition in Sprague-Dawley rats from two major suppliers. Am J Physiol Renal Physiol 302:F173-82
Bidani, Anil K; Griffin, Karen A; Epstein, Murray (2012) Hypertension and chronic kidney disease progression: why the suboptimal outcomes? Am J Med 125:1057-62

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